Intermediates for making N-aryl and N-heteroarylamide and urea derivatives as inhibitors of acyl coenzyme A: cholesterol acyl transferase (ACAT)

ABSTRACT

Compounds of the formula ##STR1## wherein R 21  and R 22  are as defined in the specification which are intermediates useful in the preparation of compounds of the formula ##STR2## and the pharmaceutically acceptable salts thereof, wherein Q and R 1  are as defined in the specification. The compounds of formula I are inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) and are useful as hypolipidemic and antiatherosclerosis agents.

This is a continuation-in-part of application Ser. No. 07/648,677 filedMar. 21, 1991, now abandoned, which is a continuation-in-part of PCTpatent application PCT/U.S. 89/04033, filed Sep. 15, 1989.

BACKGROUND OF THE INVENTION

The present invention relates to new N-aryl and N-heteroarylamide andurea derivatives, pharmaceutical compositions comprising such compounds,novel carboxylic acid and acid halide intermediates used in thesynthesis of such compounds and the use of such compounds to inhibitintestinal absorption of cholesterol, lower serum choles terol andreverse the development of atherosclerosis. The compounds are inhibitorsof acyl coenzyme A: cholesterol acyltransferase (ACAT).

Cholesterol that is consumed in the diet (dietary cholesterol) isabsorbed as free cholesterol by the mucosal cells of the smallintestine. It is then esterified by the enzyme ACAT, packaged intoparticles known as chylomicrons, and released into the bloodstream.Chylomicrons are particles into which dietary cholesterol is packagedand transported in the bloodstream. By inhibiting the action of ACAT,the compounds of this invention prevent intestinal absorption of dietarycholesterol and thus lower serum cholesterol levels. They are thereforeuseful in preventing atherosclerosis, heart attacks and strokes.

By inhibiting the action of ACAT, the compounds of the present inventionalso enable cholesterol to be removed from the walls of blood vessels.This activity renders such compounds useful in slowing or reversing thedevelopment of atherosclerosis as well as in preventing heart attacksand strokes.

Other inhibitors of ACAT are referred to in U.S. Pat. Nos. 4,716,175 and4,743,605 (a divisional of the '175 patent) and in the European PatentApplications having publication numbers 0 242 610, 0 245 687 and 0 252524. Certain ureas and thioureas as antiatherosclerosis agents arereferred to in U.S. Pat. No. 4,623,662.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR3##wherein Q is --CR² R³ R⁴ or --NR¹⁷ TR¹⁸ ; R¹ is ##STR4## R², R³ and R⁴may be the same or different, and

(a) are selected from the group consisting of hydrogen, (C₁ -C₄) alkyl,A, XR¹⁰, phenyl-(C₁ -C₇) alkyl, and (C₅ -C₆) cycloalkyl-(C₁ -C₆) alkyl,with the proviso that at least one of R², R³ and R⁴ must be A, and withthe proviso that when R¹ is a group of the formula XXVII or a group ofthe formula XXVI wherein G is nitrogen and wherein neither R⁵, R⁶ norR¹⁵ is NR¹⁹ R²⁰, (C₁ -C₆) alkylthio, (C₅ -C₇) cycloalkylthio, phenyl (C₁-C₄) alkylthio, phenylthio or heteroalkylthio, either at least one ofR², R³ and R⁴ must be XR¹⁰, or two of R², R³ and R⁴ must be A; or

(b) R² and R³ together with the carbon to which they are attached form acyclic or bicyclic system selected from the group consisting of (C₃ -C₇)cycloalkyl, (C₃ -C₇) cycloalkenyl, (C₆ -C₁₄) bicycloalkyl, (C₆ -C₁₄)bicycloalkenyl, and aryl-fused and hetero-arylfused systems containing 8to 15 carbon atoms, one ring of any of said aryl-fused andheteroaryl-fused systems being aromatic and the ring containing thecarbon to which R² and R³ are attached being non-aromatic, one of thecarbons of said aromatic ring being optionally replaced by sulfur oroxygen, one or more carbons of said non-aromatic ring being optionallyreplaced by sulfur or oxygen, and one or more carbons of said aromaticring being optionally replaced by nitrogen; one or two carbons of saidcycloalkyl or bicycloalkyl groups being optionally replaced by sulfur oroxygen, and said cyclic or bicyclic system being optionally substitutedwith one to five substituents independently selected from the groupconsisting of phenyl, substituted phenyl, (C₁ -C₆) alkyl and A, with theproviso that one and only one of said substituents is A, and one andonly one of said substituents is phenyl or substituted phenyl, saidsubstituted phenyl being substituted with one or more substituentsindependently selected from the group consisting of (C₁ -C₆) alkyl, (C₁-C₆) alkylthio, halogen and trifluoromethyl; and R⁴ is hydrogen, XR¹⁰ orA;

with the proviso that when R¹ is a group of the formula XXVII or a groupof the formula XXVI wherein G is nitrogen and wherein neither R⁵, R⁶ norR¹⁵ is NR¹⁹ R²⁰, (C₁ -C₆) alkylthio, (C₅ -C₇) cycloalkylthio, phenyl (C₁-C₄) alkylthio, phenylthio or heteroalkylthio, R² and R³, together withthe carbon to which they are attached, do not form a (C₃ -C₇) cycloalkylring containing only carbon atoms;

A is a hydrocarbon containing 4 to 16 carbons and 0, 1 or 2 doublebonds;

X is O, S, SO, SO₂, NH, NR²³ CO or NSO₂ R²⁴, wherein R²³ is hydrogen or(C₁ -C₆) alkyl and R²⁴ is (C₁ -C₆) alkyl, phenyl or (C₁ -C₃)alkyl-phenyl;

R⁵, R⁶, R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of hydrogen, fluoro, chloro, bromo, iodo, (C₁ -C₄)alkyl, (C₁-C₄) haloalkyl, (C₁ -C₄) alkoxy, (C₁ -C₆) alkylthio, (C₅ -C₇)cycloalkylthio, phenyl (C₁ -C₄) alkylthio, substituted phenylthio,heteroarylthio, heteroaryloxy, and NR¹⁹ R²⁰, wherein R¹⁹ and R²⁰ are thesame or different and are selected from the group consisting ofhydrogen, (C₁ -C₄) alkyl, phenyl, substituted phenyl, (C₁ -C₄) acyl,aroyl, and substituted aroyl, wherein said substituted phenyl andsubstituted aroyl groups are substituted with one or more substituentsindependently selected from the group consisting of (C₁ -C₆) alkyl, (C₁-C₆) alkoxy, (C₁ -C₆) alkylthio, halogen and trifluoromethyl, or R¹⁹ andR²⁰, together with the nitrogen to which they are attached, form apiperidine or morpholine ring; and wherein R⁵, R⁶, R¹⁵ and R¹⁶, whenattached to a bicyclic system, may be attached to either ring of suchsystem, with the proviso that no more than 3 non-hydrogen substituentsmay be attached to any one ring of such system;

R⁷, R⁸ and R⁹ are the same or different; R⁷ is selected from the groupconsisting of hydrogen, (C₁ -C₄) alkoxy, (C₁ -C₄) alkylthio, methyl andfluoro; and R⁸ and R⁹ are each independently selected from the groupconsisting of (C₁ -C₄) alkoxy, (C₁ -C₄) alkylthio, methyl, and fluoro;

R¹⁰ is selected from the group consisting of (C₄ -C₁₂) cycloalkyl, (C₄-C₁₂) straight or branched alkyl, (C₄ -C₁₂) cycloalkyl-(C₁ -C₆) alkyl,phenyl- (C₁ -C₆) alkyl, (substituted phenyl)-(C₁ -C₆) alkyl, (C₁ -C₆)alkyl-phenyl, (C₁ -C₆) alkyl-(substituted phenyl), substitutedthiazoles, substituted benzothiazoles, and substituted pyridines;wherein the substituents on the substituted phenyl, substitutedthiazoles, substituted benzothiazoles and substituted pyridines areselected from the group consisting of (C₁ -C₄) alkoxy, (C₁ -C₄)alkylthio, (C₁ -C₆) alkyl, halo and trifluoromethyl;

B, D, E and G are selected from the group consisting of nitrogen andcarbon, with the proviso that one or more of B, D and E is nitrogen, andwith the proviso that when G is nitrogen, the group XXVI is attached tothe nitrogen of formula I at the 4 or 5 position of the pyrimidine ring(designated by a and b);

and R¹⁷ and R¹⁸ are each independently selected from the groupconsisting of (C₄ -C₁₂) straight or branched alkyl, phenyl-(C₁ -C₄)alkyl, and (C₁ -C₆) alkylphenyl-(C₁ -C₆) alkyl;

with the proviso that when Q is NR¹⁷ R¹⁸, R¹ is a group of the formulaXXVI or XXIV, or a group of the formula XXVII wherein R⁷, R⁸ and R⁹ areeach methoxy.

Examples of said aryl-fused and heteroaryl--fused systems are:

1,2,3,4-tetrahydronapthalene,

5,6,7,8,9-pentahydrobenzocycloheptene,

5,6,7,8,9,10-hexahydrobenzocyclooctene,

4,5,6-trihydro-1-thiapentalene,

4,5,6-trihydro-2-thiapentalene,

4,5,6,7-tetrahydrobenzo[b]thiophene,

4,5,6,7-tetrahydrobenzo[c]thiophene,

4,5,6-trihydro-1-oxapentalene,

4,5,6,7-tetrahydrobenzo[b]furan,

4,5,6-trihydro-1-azapentalene,

4,5,6,7-tetrahydrobenzo[b]pyrrole,

4,5,6-trihydro-1-oxa-3-azapentalene,

4,5,6,7-tetrahydrobenzo[d]oxazole,

4,5,6-trihydro-1-thia-3--azapentalene

4,5,6,7-tetrahydrobenzo[d]thiazole,

4,5,6-trihydro-1-oxa-2-azapentalene,

4,5,6,7-tetrahydrobenzo[d]oxazole,

4,5,6-trihydro-1-thia-2-azapentalene,

4,5,6,7-tetrahydrobenzo[d]thiazole,

4,5,6-trihydro-1,2-diazapentalene,

4,5,6,7-tetrahydrobenzo[d]pyrazole,

4,6-diazaindane and

5,6,7,8-tetrahydroquinazoline.

Unless otherwise indicated, the term "halo", as used herein, includesfluoro, chloro, bromo and iodo.

Unless otherwise indicated, the term "alkyl" as used herein, may bestraight, branched or cyclic, and may include straight and cyclicmoieties as well as branched and cyclic moleties.

Unless otherwise indicated, the term "one or more substituents", as usedherein, refers to from one to the maximum number of substituentspossible based on the number of available bonding sites.

The term "one or more carbons of said non-aromatic ring", as usedherein, refers to from one to all of the carbon atoms that are part ofthe non-aromatic ring of any of the aryl-fused or heteroaryl-fusedsystems described above, and not part of the aromatic ring of saidaryl-fused system.

The term "one or more carbons of said aromatic ring", as used herein,refers to from one to all of the carbon atoms that are part of thearomatic ring of any of the aryl-fused and heteroaryl-fused systemsdescribed above, or are part of both said aromatic and non-aromaticrings of said aryl-fused and heteroaryl-fused system.

The compounds of formula I may have optical centers and therefore mayoccur in different stereoisomeric configurations. The invention includesall stereoisomers of such compounds of formula I, including mixturesthereof.

The present invention also relates to compounds of the formula ##STR5##wherein Z is hydroxy, halo or other acylation functional group such asacyloxy wherein said acyl group is R² C(═O)O-- or different; R², R³ andR⁴ are each independently selected from the group consisting of (C₆-C₁₆) alkyl, (C₆ -C₁₆) alkenyl containing 1 or 2 double bonds,phenyl-(C₁ -C₆) alkyl, (C₅ -C₆) cycloalkyl-(C₁ -C₆) alkyl, XR¹⁰, andhydrogen, with the proviso that at least one of R², R³ and R⁴ is (C₆-C₁₆) alkyl or (C₆ -C₁₆) alkenyl containing 1 or 2 double bonds; or R²and R³, together with the carbon to which they are attached, form acyclic or bicyclic ring system selected from the group consisting of##STR6## and aryl-fused and heteroaryl-fused systems containing 8 to 15carbon atoms, one ring of any of said aryl-fused and heteroaryl-fusedsystems being aromatic and the other ring containing the carbon to whichR² and R³ are attached being non-aromatic, one of the carbons of saidaromatic ring being optionally replaced by sulfur or oxygen, one or morecarbons of said non-aromatic ring being optionally replaced by sulfur oroxygen, and one or more carbons of said aromatic ring being optionallyreplaced by nitrogen;

and wherein R⁴ is hydrogen, A or XR¹⁰ ; A is a hydrocarbon containing 4to 16 carbons and 0, 1 or 2 double bonds; X is oxygen or sulfur; R¹⁰ isselected from the group consisting of (C₄ -C₁₂) cycloalkyl, (C₄ -C₁₂)straight or branched alkyl, (C₄ -C₁₂) cycloalkyl-(C₁ -C₆) alkyl,phenyl-(C₁ -C₆) alkyl, (substituted phenyl)-(C₁ -C₆) alkyl, (C₁ -C₆)alkyl-phenyl, (C₁ -C₆) alkyl-(substituted phenyl),substituted thiazoles,substituted benzothiazoles, and substituted pyridines, wherein thesubstituents on the substituted phenyl, substituted thiazoles,substituted benzothiazoles and substituted pyridines are selected fromthe group consisting of (C₁ -C₄) alkoxy, (C₁ -C₄) alkylthio, (C₁ -C₆)alkyl, halo and trifluoromethyl; R¹¹ is (C₆ -C₁₂) alkyl or (C₆ -C₁₂)alkenyl containing 1 or 2 double bonds; n and m are each independently 1or 2; o and p are each independently 0, 1 or 2; each broken linerepresents an optional double bond; and each asterisk represents thecarbon to which R² and R³ are attached; with the proviso that when R²and R³ form any of ring systems XVIII, XIX and XX, R⁴ is A or XR¹⁰, andwhen R² and R³ form any of ring systems XXI, XXII and XXIII, R⁴ ishydrogen; and with the proviso that when R² and R³ do not form a ringsystem, no more than one of R², R³ and R⁴ is hydrogen. The compounds offormula II are intermediates used in the synthesis of compounds of theformula I.

Specific compounds of the formula II are: 2-(hexylthio) octanoic acid,2-(hexylthio) nonanoic acid, 2-(hexylthio) decanoic acid, 2-(heptylthio)octanoic acid, 2-(heptylthio) nonanoic acid, 2-(heptylthio) decanoicacid, 2-nonylindan-2-yl carboxylic acid, 2-decylindan-2-yl carboxylicacid, 2-octyl-1,2,3,4-tetrahydronaphth-2-yl carboxylic acid and2-nonyl-1,2,3,4-tetrahydronaphth-2-yl carboxylic acid.

The present invention also relates to compounds of the formula ##STR7##wherein R²¹ is (C₁ -C₃) alkyl and R²² is hydrogen or (C₁ -C₃) alkyl.

Preferred compounds of formula I are those wherein R¹ is2,4,6-trifluorophenyl, 2,4,6-trimethoxyphenyl, 6-methoxyquinolin-5-yl,6-methylthioquinolin-5-yl, 6-methoxy-isoquinolin-5-yl,6-methylthioisoquinolin-5-yl, 6-methylthio-8-acetaminoquinolin-5-yl,2-methyl-4,6-di(methylthio)pyrimidin-5-yl, and6-methyl-2,4-di(methylthio)pyridin-3-yl.

Other preferred compounds of formula I are those wherein:

R² is hexylthio, R³ is octyl and R⁴ is hydrogen; or

R² and R³ together with the carbon to which they are attached form anindan-2-yl ring, and R⁴ is 2-decyl; or

R² and R³ together with the carbon to which they are attached form a1,2,3,4-tetrahydronaphth-2-yl ring and R⁴ is nonyl.

Specific preferred compounds of formula I are:

N-(2,4,6-trifluorophenyl)-2-(hexylthio) octanoicamide;

N-(2,4,6-trimethoxyphenyl)-2-(hexylthio) octanoic amide;

N-(2,4,6-trimethoxyphenyl)-2-(6-ethoxybenzothiazol-2-yl) decanoic amide;

N-(6-methoxyquinolin-5-yl)-2-(hexylthio) decanoic amide;

N-(6-methylthioquinolin-5-yl)-2-(hexylthio) decanoic amide;

N-(6-methoxyisoquinolin-5-yl)-2-(hexylthio) decanoic amide;

N-(6-methylthio-8-acetaminoquinolin-5-yl)-2(hexylthio)decanoic amide;

N-(6-methylthioisoquinolin-5-yl)-2-(hexylthio) decanoic amide;

N-(6-methylisoquinolin-5-yl)-2-(hexylthio) decanoic amide;

N-(6-methylthioquinolin-5-yl)-2-(4-(3-methylpropyl)phenoxy) nonanoicamide;

(2 S)-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2 -hexylthiodecanoicamide;

(2S) -N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2-hexylthiodecanoic amide;

(2S)-N-[6-(methylthio)quinolin-5-yl]-2-hexylthiodecanoic amide;

N-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-2-hexylthiodecanoicamide;

N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hexylthiodecanoic amide;

N-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-2,2-dimethyldocecanoicamide;

N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2,2-dimethyldodecanoicamide;

N'-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-N-[4-(3-methylbutyl)benzyl]-N-cycloheptylurea;

N'-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-N-[4-(3-methylbutyl)benzyl]-N-heptylurea;

N'-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-N-[4-(3-methylbutyl)benzyl]-N-cycloheptylurea;

N'-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-N-[4-(3-methylbutyl)benzyl]-N-heptylurea;

N-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-4,5-dimethyl-trans-2-heptylcyclohex-4-ene-carboxamide;

N-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-2 -heptylnonanoic amide;

N-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]pentadecanoic amide;

N-[2,4-bis(methylthio)-6-methylpyridin-3-yl-]pentadecanoic amide;

N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-(Z)-9-octadecenoic amide;

N-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-(Z)-9-octadecenoic amide;

N-[4,6-bis(methylthio)-2-methylpyrimidin-5-yl]-trans-3-nonyl-1,2,3,4-tetrahydro-2-naphthoicamide;

N-[4,6-bis(methylthio)pyrimidin-5-yl]-trans-3-nonyl-1,2,3,4-tetrahydro-2-naphthoicamide;

N-(2,4,6-trimethoxyphenyl)-2-nonyl-1,2,3,4-tetrahydronapth-2-ylcarboxamide;

N-(2,4,6-trifluorophenyl)-2-nonyl-1,2,3,4-tetrahydronapth-2-ylcarboxamide;

N-(2,4,6-trifluorophenyl)-2-nonylindan-2-yl carboxamide;

N-(2,4,6-trimethoxyphenyl)-6-trans-heptyl-3,4-dimethylcyclohex-2-enylcarboxamide;

N-(2,4,6-trimethoxyphenyl)-2-nonylbicyclo[2.2.1]-hept-5-en-2-ylcarboxamide;

N-(6-methylthioquinolin-5-yl)-2-octyl-1,3-dithian-2-yl carboxamide;

N-(2-methyl-4,6-dimethylthiopyrimidin-5-yl)-2-hexylthiodecanoic amide;

N-(2,4,6-trimethoxyphenyl)-N'-(4-(3-methylbutyl)phenylmethyl)-N'-heptylurea;

N-(2,4,6-trimethoxyphenyl)-N'-(4-(2,2-dimethylpropyl)phenylmethyl)-N'-heptylurea;

N-(isoquinolin-5-yl)-N'-(4-(3-methylbutyl)phenylmethyl)-N'-heptylurea;

N-(quinolin-5-yl)-N'-(4-(3-methylbutyl)phenylmethyl)-N'-heptylurea; and

N-(6-methoxyquinolin-5-yl)-N'-(4-(3-methylbutyl)phenylmethyl)-N'-heptylurea.

Other compounds of formula I are:

N-(2-methoxy-6-methylphenyl)-2-(4-propylphenyl)sulfonylundecanoic amide;

N-(3-methyl-6-trifluoromethylquinolin-5-yl)-2-(2,5-dimethylphenoxy)decanoicamide;

N-(6,7-(methylenedioxy)isoquinolin-5-yl)-2-(thiazol-2-yl)methoxynonanoicamide;

N-(2,6-dimethoxyphenyl)-2,2-di(isopropylthio)-octanoic amide;

N-(3-chloro-8-isobutylquinolin-5-yl)-2-(3-ethoxyphenyl)thio-2-propylheptanoicamide;

N-(4-methyl-6,7-difluoroisoquinolin-5-yl)-1-methyl-5-octyl-2,7-dioxabicyclo[2.2.1]heptan-5-ylcarboxamide;

N-(2,4,6-trimethoxyphenyl)-2-propylthiohexadec9-enoic amide;

N-(6-isopropylthioquinolin-5-yl)-2-(4-ethylthiophenoxy)non anoic amide;

N-(6-methoxyisoquinolin-5-yl)-2-[5-chlorobenzthiazol-2-yl) thio]octanoicamide;

N-(2,4,6-trifluorophenyl)-2-[(3,5-dimethylbenzoyl)amino]octanoic amide;

N-(8-acetamino-6-methoxyquinolin-5-yl)-2-hexylthiodecanoic amide;

N-(8-amino-6-methoxyquinolin-5-yl)-2-hexylthiodecanoic amide;

N-(8-amino-6-methylthioquinolin-5-yl)-2-hexylthiodecanoic amide;

N-(8-(2,2-dimethylpropionyl)amino-6-methoxyquinolin-5-yl)-2-hexylthiodecanoicamide;

N-(8-(2,2-dimethylpropionyl)amino-6-methoxyquinolin-5-yl)-2-hexylthiodecanoicamide;

N-(6-methylthioquinolin-5-yl)-2-hexyloxydecanoic amide;

N-(8-acetamino-6-methylthioquinolin-5-yl)-2-hexyloxydecanoic amide;

N-(6-methylthioquinolin-5-yl)-2-heptylnonanoic amide;

N-(8-acetamino-6-methylthioquinolin-5-yl)-2-heptylnonanoic amide;

N-(8-acetaminoquinol in-5-yl)-2-hexylthiodecanoic amide;

N-(8-aminoquinolin-5-yl)-2-hexylthiodecanoic amide;

N-(6-acetaminoquinolin-5-yl)-2-hexylthiodecanoic amide;

N-(6-aminoquinolin-5-yl)-2-hexylthiodecanoic amide;

N-(4,6-dimethylthiopyrimidin-5-yl)-2-hexylthiodecanoic amide;

N-(4,6-diethylthiopyrimidin-5-yl)-2-hexylthiodecanoic amide;

N-(4-methoxy-6-ethylthiopyrimidin-5-yl)-2-hexylthiodecanoic amide;

N-(4-ethoxy-6-methylthiopyrimidin-5-yl)-2-hexylthiodecanoic amide;

N-(4-ethoxy-6-ethylthiopyrimidin-5-yl)-2-hexylthiodecanoic amide;

N-(4-methoxy-6-ethoxyethylthiopyrimidin-5-yl)-2hexylthiodecanoic amide;

N-(4-methoxy-6-butylthiopyrimidin-5-yl)-2-hexylthiodecanoic amide;

N-(2,4-dimethylthio-6-methylpyrimidin-5-yl)-2heptylnonanoic amide;

N-(2-amino-4-methoxy-6-methylthiopyrimidin-5-yl)-2-hexylthiodecanoicamide;

N-(2-acetamino-4-methoxy-6-methylthiopyrimidin-5-yl)-2-hexylthiodecanoicamide;

N-[4-methoxy-6-(2-furylmethylthio)pyrimidin-5-yl]-2-hexylthiodecanoicamide;

N-[4-methoxy-6-(2-propylthio)pyrimidin-5-yl]-2-hexylthiodecanoic amide;

N-(2-butylthio-4-methylpyridin-3-yl)-2-hexylthiodecanoic amide;

N-[2-(4-methoxyphenylthio)-4-methylpyridin-3-yl]-2-hexylthiodecanoicamide;

N-[2-(2-furylmethylthio)-4-methylpyridin-3-yl]-2-hexylthiodecanoicamide;

N-(2-ethylthio-4-methylpyridin-3-yl)-2-hexylthiodecanoic amide;

N-(6-methoxyquinolin-5-yl)-9-octadecenoic amide;

N-(6-fluoroquinolin-5-yl)-9-octadecenoic amide;

N-(6-methylthioquinolin-5-yl)-9-octadecenoic amide;

N-(8-acetamino-6-methylthio-quinolin-5-yl)-9-octadecanoic amide;

N-(2-ethylthio-4-methylpyridin-3-yl)-4,5-dimethyltrans-2-nonylcyclohex-4-enecarboxamide;and

N-(4,6-dimethylthiopyrimidin-5-yl)-2-decylindane-2-carboxamide.

The present invention also relates to all radiolabelled forms of thecompounds of the formulae I, II and XXVIII. Such radiolabelled compoundsare useful as research and diagnostic tools in metabolismpharmacokinetic studies and in binding assays in both animals and man.

The present invention also relates to a pharmaceutical composition forinhibiting ACAT, inhibiting intestinal absorption of cholesterol,reversing or slowing the development of atherosclerosis, or lowering theconcentration of serum cholesterol in a mammal, including a human,comprising an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, effective in inhibiting ACAT,inhibiting intestinal absorption of cholesterol, reversing or slowingthe development of atherosclerosis, or lowering the concentration ofserum cholesterol, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for inhibiting ACAT,inhibiting intestinal absorption of cholesterol, reversing or slowingthe development of atherosclerosis, or lowering the concentration ofserum cholesterol in a mammal, including a human, comprisingadministering to a mammal an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, effective in inhibiting ACAT,inhibiting intestinal absorption of cholesterol, reversing or slowingthe development of atherosclerosis, or lowering the concentration ofserum cholesterol.

Examples of pharmaceutically acceptable acid addition salts of thecompounds of formula I salts are the salts of hydrochloric acid,p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid,salicyclic acid, oxalic acid, hydrobromic acid, phosphoric acid,methanesulfonic acid, tartaric acid, di-p-toluoyl tartaric acid, andmandelic acid.

DETAILED DESCRIPTION OF THE INVENTION

Reaction schemes 1-4 below illustrate the synthesis of the compounds ofthis invention. The compounds of formula I designated in the reactionschemes by the formulae IA, IB, IC, and ID, depending on the method bywhich they prepared. Scheme 5 below illustrates the synthesis of certain5-aminoquinolines and 5-aminoisoquinolines used as reactants in scheme1-4.

Except where otherwise stated, Q, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, R¹⁸, n, m, o, p, X, A, B, D, and G in thereaction schemes and discussion that follows are defined as above.##STR8##

Scheme 1 represents the synthesis of amides of the present inventionhaving the formula IA, i.e., compounds of the formula I wherein Q is--CR² R³ R⁴, from the corresponding carboxylic acid having the formulaIII. An acid of formula III is first converted to the corresponding acidhalide of formula IV, wherein W is chloro or bromo, by reacting it witha chlorinating or brominating agent. Examples of suitable chlorinatingand brominating agents are oxalyl chloride, oxalyl bromide, thionylchloride, thionyl bromide, phosphorous trichloride, phosphoroustribromide, phosphorous pentachloride, phosphorous pentabromide,phosphorous oxychloride, and phosphorous oxybromide. This reaction istypically carried out in the absence of a solvent or, alternatively, inthe presence of a halogenated hydrocarbon solvent such as methylenechloride, for from about 0.5 to 48 hours (preferably from about 2 to 18hours) at a temperature from about 0°-250° C. (preferably at the refluxtemperature of the reaction mixture). The acid halide so formed is thenconverted to the corresponding amide of the formula IA by reacting itwith an amine of the formula R¹ NH₂ and an acid scavenger such asdimethylaminopyridine, pyridine or triethylamine. This reaction istypically carried out in the absence of a solvent or in the presence ofan inert solvent such as tetrahydrofuran or methylene chloride for fromabout 0.25 to 144 hours (preferably from about 2 to 72 hours) at atemperature from about -78° to 350° C. (preferably from about -20 to thereflux temperature of the reaction mixture).

Compounds of the formula I, wherein Q is --CR² R³ R⁴, R² is XR¹⁰, one ofR³ and R⁴ is hydrogen and the other is selected from hydrogen, (C₁ -C₄)alkyl or A, i.e., compounds of the formula IB, may be prepared asillustrated in scheme 2. Referring to scheme 2, a carboxylic acid of theformula V, wherein one of R³ and R⁴ is hydrogen and the other isselected from hydrogen, (C₁ -C₄) alkyl or A, is reacted for about 3hours with thionyl chloride using no solvent, at the reflux temperatureof the reaction mixture. Bromine and a catalytic amount of iodine arethen added to the reaction mixture, and the resulting mixture is broughtto reflux. After refluxing for about 18 hours, ethanol is added and themixture is refluxed for about 1 more hour to produce a bromoester of theformula VI, wherein R³ and R⁴ are defined as they are for formula Vabove. The bromoester of formula VI is then converted to an ester havingthe same formula as formula VI except that the substituent --Br isreplaced by the substituent --XR¹⁰, (hereinafter referred to as formulaVI'), by reacting it with a compound of the formula HXR¹⁰ and a basesuch as potassium carbonate or sodium hydride in an aprotic, polarsolvent such as dimethylformamide, acetone or tetrahydrofuran, for about0.5 to 48 hours (preferably from about 4 to 18 hours) at a temperaturefrom about -78° to 350° C. (preferably from about 0° C. to the refluxtemperature of the reaction mixture). An acid of the formula VII,wherein R³ and R⁴ are defined as they are for formulas V and VI above,is then prepared by reacting the ester having formula VI' with ahydroxide such as sodium hydroxide. This reaction is typically carriedout overnight in an lower alcohol solvent such as methanol or ethanol,at a temperature from about -78° to 350° C. (preferably from about 20°C. to the reflux temperature of the reaction mixture).

The acid of formula VII so prepared is then converted to an amide of theformula IB, wherein R³ and R⁴ are defined as they are for formulae V, VIand VII above, by the acid to amide synthesis illustrated in scheme 1and described above.

Compounds of the formula IB, may be prepared, alternatively, by thefollowing method. A compound of the formula V, as illustrated in scheme2 and defined above, is reacted with thionyl chloride followed bybromine and a catalytic amount of iodine as described above, butquenching the reaction with water instead of ethanol, to form a compoundof the formula HOOCCBrR³ R⁴, wherein R³ and R⁴ are defined as they arefor formula V. This compound is then converted, sequentially, to thecorresponding acid chloride of the formula ClCOCBrR³ R⁴ and thecorresponding amide of the formula R¹ NHCOCBrR³ R⁴, wherein R³ and R⁴are defined as they are for formula V, by the acid to amide synthesisillustrated in scheme 1 and described above. The amide of the formula R¹NHCOCBrR³ R⁴ so formed is then reacted with a compound of the formulaHXR¹⁰ and a base such as potassium carbonate and sodium hydride to forma compound having the formula IB, wherein R³ and R⁴ are defined as theyare for formula V. This reaction is typically carried out in an aprotic,polar solvent such as dimethylformamide, acetone or tetrahydrofuran, forfrom about 0.5 to 48 hours (preferably from about 4 to 18 hours). Thereaction may be carried out at temperatures ranging from about -78° to350° C. (preferably from about 0° C. to the reflux temperature of thereaction mixture).

Scheme 3 illustrates the preparation of compounds of formula I, whereinQ is CR² R³ R⁴, R⁴ is hydrogen or A, and R² and R³, together with thecarbon to which they are attached, form the bicyclic ring system##STR9## wherein the asterisk designates the carbon to which R² and R³are attached, and each of R¹² and R¹³ are independently selected fromthe group consisting of hydrogen and (C₁ -C₄) alkyl, or R¹² and R¹³,together with the carbons to which they are attached, form a benzenering.

As illustrated in scheme 3, a Dieis-Alder reaction is carried outbetween an acid of the formula XIII, wherein R¹¹ is A, hydrogen, phenylor substituted phenyl, and wherein R¹¹ and the carboxyl group are transto each other, and a diene of the formula IX, wherein R¹² and R¹³ are asdefined above. This reaction is typically carried out in a hydrocarbonsolvent such as toluene, using a catalytic amount of an antioxidant suchas hydroquinone. The reagents are generally reacted for about 1 to 10days (preferably for about 3 to 5 days) in a sealed, high pressureapparatus at a temperature from about room temperature to 350° C.(preferably from about 100° to 150° C.). The reaction yields an acid ofthe formula X, which can be converted to the corresponding amide of theformula IC, wherein the carbons to which R¹² and R¹³ are attached arebonded by a carbon-carbon double bond, by the acid to amide synthesisillustrated in scheme 1 and described above. The amide of formula IC soformed can be converted to an amide of the formula IC, wherein thecarbons to which R¹² and R¹³ are attached are bonded by a carbon-carbonsingle bond, by reacting it with a reducing agent such as hydrogen.Typically, the reduction is carried out using hydrogen gas in a highpressure apparatus, in an inert solvent such as acetic acid, and in thepresence of a hydrogenation catalyst such as palladium on carbon. Thereduction maybe carried out at temperatures ranging from about -20° to250° C. (preferably at room temperature). Fifty p.s.i. of hydrogen isthe preferred pressure, through pressures greater than or equal to 1atmosphere are suitable. The corresponding compound of formula IC,wherein the carboxyl group and R¹¹ are cis to each other, may beprepared in a similar manner, but using the corresponding cis isomer ofthe acid of formula XIII.

When the procedure of scheme 3 described above is used to prepare acompound of formula IC wherein R¹² and R¹³, together with the carbon towhich they are attached, form a benzene ring, the diene of formula IX isgenerally generated in situ in the presence of the acid of formula XIIIor its ester by heating a mixture of 1,3-dihydrobenzo[c]thiophene2,2-dioxide and such acid or ester. This reaction is typically carriedout at a temperature of from about 235° to 300° C. (preferably fromabout 250° to 265° C.) under nitrogen for approximately from 0.5 to 24hours (preferably for about 2 hours).

Scheme 4 illustrates the preparation of compounds of the formula I,wherein Q is --CR² R³ R⁴, R⁴ is (C₁ -C₄) alkyl or A, and R² and R³ areeach independently selected from the group consisting of hydrogen, (C₁-C₄) alkyl, A or XR¹⁰ ; or R² and R³, together with the carbon to whichthey are attached, form a cyclic or bicyclic system selected from thegroup consisting Of (C₃ -C₇) cycloalkyl, (C₆ -C₁₄) bicycloalkyl, one ortwo carbons of said cycloalkyl and bicycloalkyl groups being optionallyreplaced with oxygen or sulfur; and aryl-fused and heteroaryl-fusedsystems containing 8 to 15 carbon atoms, one ring of any of saidaryl-fused and heteroaryl-fused systems being aromatic and the ringcontaining the carbon to which R² and R³ are attached beingnon-aromatic, one of the carbons of said aromatic ring being optionallyreplaced by sulfur or oxygen, one or more carbons of said non-aromaticring being optionally replaced by sulfur or oxygen, and one or morecarbons of said aromatic ring being optionally replaced by nitrogen. Italso illustrates the preparation of compounds of the formula I, whereinQ is --CR² R³ R⁴, R⁴ is XR¹⁰, and R² and R³, together with the carbon towhich they are attached, form a cyclic or bicyclic system as definedimmediately above. All compounds of the invention illustrated in scheme4 are designated by the formula ID and are prepared by the followingprocedure.

An acid of the formula XI, wherein R² and R³ are each independentlyselected from the group consisting of hydrogen, (C₁ -C₄) alkyl, A orXR¹⁰, or R² and R³ together with the carbon to which they are attached,form a cyclic or bicyclic system as defined immediately above, isreacted with a base such as lithium diisopropylamide orhexamethyldisilazide, with or without an additive such ashexamethylphosphorous triamide, in a dry inert solvent such astetrahydrofuran, and then reacted with a compound of the formula R⁴ Hal,wherein Hal is halogen and R⁴ is (C₁ -C₇) alkyl or A. The reaction istypically carried out at a temperature from about -78° to 40° C.(preferably from about -78° C. to room temperature) for about 0.5 to 48hours (preferably for about 1.5 to 17 hours: 0.5 to 1 hour to generatethe dianion of formula XI and 1 to 16 hours for the alkylation). Theproduct of the reaction is an acid of the formula XII, wherein R² and R³are as defined immediately above, and R⁴ is (C₁ -C₇) alkyl or A. Theacid of formula XII so formed may be converted to the correspondingamide of the formula ID, wherein R² and R³ are as defined immediatelyabove and R⁴ is (C₁ -C₇) alkyl or A, by the acid to amide synthesisillustrated in scheme 1 and described above.

Compounds of the formula ID, wherein R⁴ is XR¹⁰, are prepared by thesame procedure as that described above for the preparation of compoundsof the formula ID wherein R⁴ is (C₁ -C₇) alkyl or A, with onemodification. The dianion of formula XI is reacted with a compound offormula R¹⁰ SSR¹⁰ instead of HalR⁴. This reaction produces an acid ofthe formula XII, wherein R⁴ is XR¹⁰. The acid of the formula XII soformed can then be converted to the corresponding amide of formula ID bythe acid to amide synthesis illustrated in scheme 1 and described above.

The aminopyrimidine and aminopyridine intermediates used in the presentinvention are known in the literature or may be prepared by methodsknown in the art from intermediates that are known in the literature orcommercially available. References for the preparation of many of thepyrimidine and pyridine intermediates can be found in the monographs"The Pyrimidines", ed. by D. J. Brown (1962) and "Pyridine and itsDerivatives", ed. by R. A. Abramovitch (1961), Interscience Publishers,Inc., New York, N.Y., and their supplements. The preparation of certainof these intermediates is described in greater detail below.

2,6-Disubstituted-5-amino-pyrimidine derivatives may be prepared byreacting the appropriately substituted 4,6-dihydroxypyrimidine with anitrating agent such as fuming nitric acid in acetic acid at atemperature from about 15° C. to about 40° C. for a period of about 1 toabout 5 hours. The resulting 5-nitropyrimidines are converted to the2,4-dichloro-5nitropyrimidine intermediates using a chlorinating agentsuch as phosphoryl chloride, alone or in the presence of a base,preferably diethylaniline, at a temperature from about 100° to about115° C. for a period of about 0.5 to about 2 hours. Procedures forcarrying out these transformations are described in J. Chem. Soc., 3832(1954).

The 2,6-bis(alkylthio)-5-nitropyrimidine derivatives may be prepared byreacting the appropriate dichloro intermediate with two equivalents ofsodium alkylthiolate in a solvent such as dimethylformamide or,preferably, methanol, for about 4 to about 16 hours at a temperaturefrom about 0° to about 30° C., preferably at ambient temperature.Monosubstitution of the dichloro intermediate is then accomplished byusing one equivalent of nucleophile, at a reaction temperature of about0° to about 100° C., depending on the reactivity of the nucleophile, inan inert solvent such as dimethyl-formamide or tetrahydrofuran, for aperiod of about 4 to about 16 hours.

The resulting monochloro derivative is then reacted with one equivalentof a different nucleophile to yield a disubstituted derivative withdifferent substitutents on the carbon atoms at positions 2 and 4. The2,6-disubstituted-5-nitropyrimidine is reduced using a reducing agentsuch as stannous chloride in concentrated hydrochloric acid or hydrogengas with an appropriate catalyst, to yield the corresponding5-aminopyrimidine derivative.

The novel pyridines of formula XXVIII and other2,4-disubstituted-3-aminopyridine derivatives may be prepared byreacting the appropriate 2,4-dihydroxypyridine with a nitrating agentsuch as concentrated nitric acid at 80°-100° C. for 15-60 minutes. Forexample, the preparation of 2,4-dihydroxy-6-methyl-3-nitropyridine isdescribed in J. Heterocyclic Chem., 1970, 7, 389. The resulting2,4-dihydroxy-3-nitro- pyridine is sequentially converted to the2,4-dichloro-3-nitropyridine, 2,4-disubstituted-3-nitropyridine and2,4-disubstituted-3-aminopyridine derivatives, using reaction conditionssimilar to those described above for the pyrimidine series.

The preparation of certain 5-aminoquinolines and 5-aminoisoquinolinesused as reactants in scheme 1 is illustrated in scheme 5. Referring toscheme 5, 5-aminoquinolines and isoquinolines of the formulae XV andXVII may be prepared as follows. A quinoline or isoquinoline of theformula XIII is nitrated at the 5 position, respectively, by reacting itwith a nitrating agent such as nitric acid or potassium nitrate with orwithout an acid catalyst such as sulfuric acid, for from about 2 to 16hours at a temperature from about 0°-100° C. The nitro compound offormula XIV so formed is then reduced using a reducing agent such asstannous chloride, iron, zinc, or hydrogen gas with an appropriatecatalyst, with or without an acid catalyst such as hydrochloric acid,for from about 2 to 16 hours at a temperature from about 0°-100° C., toyield the corresponding 5-aminoquinoline or 5-aminoisoquinoline offormula XV.

Compounds of the formula XVII, wherein R⁵ is --SR¹⁴ and is attached tothe quinoline or isoquinoline ring at the 6 position, and wherein R¹⁴ is(C₁ -C₆) alkyl, (C₅ -C₇) cycloalkyl, phenyl (C₁ -C₄) alkyl, phenyl,substituted phenyl, heteroaryl, or substituted heteroaryl, may beprepared as follows. A compound of the formula XIV, wherein R⁵ is --Cland is attached to the quinoline or the isoquinoline ring at the 6position, is reacted with a compound of the formula R¹⁴ SH, wherein R¹⁴is as defined above, and a base such as sodium hydride, or such compoundof the formula XIV is reacted with a compound of the formula R¹⁴ SNa,wherein R¹⁴ is as defined above, in an inert solvent such astetrahydrofuran, for about 4 to 16 hours at a temperature of from about-10° C. to room temperature. The preferred temperature is -10° C. Thisreaction yields a compound of the formula XVI, which is then convertedto the corresponding 5-aminoquinoline or isoquinoline of the formulaXVII by the method described above for reduction of compounds of formulaXIV.

An alternated and preferred method of making compounds of the formula Iwherein Q is --CR² R³ R⁴, R⁴ is hydrogen, R³ is A, R⁴ is alkylthio,phenylthio or heteroalkylthio, and R¹ is a group of the formulae XXIV orXXVII is described in Examples 261-263. Variations of this procedure aredescribed in greater detail in the U.S. patent application of Kelly etal., assigned in common and filed concurrently with the presentapplication.

The urea compounds of the formula I, wherein Q is --NR¹⁷ R¹⁸, may beprepared by reacting a secondary amine of the formula NHR¹⁷ R¹⁸ with acompound of the formula R¹ NCO. The reaction is typically carried out atambient temperature in a hydrocarbon solvent such as hexane. Secondaryamines of the formula NHR¹⁷ R¹⁸ may be prepared by a variety of methodswell known in the art. (See, e.g., Vogel's Textbook of Practical OrganicChemistry, Longmen, Inc., New York, pp. 564-575 (4 ed. 1978).

Except where otherwise noted, pressure is not critical in any of theabove reactions. Preferred temperatures for the above reactions werestated where known. In general, the preferred temperature for eachreaction is the lowest temperature at which product will be formed. Thepreferred temperature for a particular reaction may be determined bymonitoring the reaction using thin layer chromatography.

The novel compounds of formula I and the pharmaceutically acceptablesalts thereof are useful as inhibitors of acyl coenzyme A: cholesterolacyltransferase (ACAT). As such they inhibit intestinal absorption ofcholesterol in mammals and are useful in the treatment of high serumcholesterol in mammals, including humans. As used herein, treatment ismeant to include both the prevention and alleviation of high serumcholesterol. The compound may be administered to a subject in need oftreatment by a variety of conventional routes of administration,including orally, parenterally and topically. In general, thesecompounds will be administered orally or parenterally at dosages betweenabout 0.5 and about 30 mg/kg body weight of the subject to be treatedper day, preferably from about 0.08 to 5 mg/kg. For an adult human ofapproximately 70 kg of body weight, the usual dosage would, therefore,be about 3.5 to about 2000 mg per day. However, some variation in dosagewill necessarily occur depending on the condition of the subject beingtreated and the activity of the compound being employed. The personresponsible for administration will, in any event, determine theappropriate dose for the individual subject.

A compound of formula I or a pharmaceutically acceptable salt thereofmay be administered alone or in combination with pharmaceuticallyacceptable carriers, in either single or multiple doses. Suitablepharmaceutical carriers include inert solid diluents or fillers, sterileaqueous solution and various organic solvents. The resultingpharmaceutical compositions are then readily administered in a varietyof dosage forms such as tablets, powders, lozenges, syrups, injectablesolutions and the like. These pharmaceutical compositions can, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus, for purposes of oral administration,tablets containing various excipients such as sodium citrate, calciumcarbonate and calcium phosphate may be employed along with variousdisintegrants such as starch, alginic acid and certain complexsilicates, together with binding agents such as polyvinylpyrrolidone,sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, sodium lauryl sulfate and talc are often useful fortabletting purposes. Solid compositions of a similar type may also beemployed as fillers in soft and hard filled gelatin capsules. Preferredmaterials for this include lactose or milk sugar and high molecularweight polyethylene glycols. When aqueous suspensions or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter or dyes and, if desired, emulsifying or suspending agents,together with diluents such as water, ethanol, propylene glycol,glycerin and combinations thereof.

For parenteral administration, solutions of a compound of formula I or apharmaceutically acceptable salt thereof in sesame or peanut oil,aqueous propylene glycol, or in sterile aqueous solution may beemployed. Such aqueous solutions should be suitably buffered ifnecessary and the liquid diluent first rendered isotonic with sufficientsaline or glucose. Such solutions are especially suitable forintravenous, intramuscular, subcutaneous and intraperitionealadministration. In this connection, the sterile aqueous media employedare all readily available by standard techniques known to those skilledin the art.

The activity of the compounds of the present invention as ACATinhibitors may be determined by a number of standard biological orpharmacological tests. For example, the following procedure was used todetermine the ACAT inhibiting activity of compounds of formula I. ACATwas assayed in microsomes isolated from chow fed Sprague-Dawley ratsaccording to Bilheimer, J. T., Meth. Enzymol., 111, ps 286-293 (1985),with minor modifications. Microsomes from rat liver were prepared bydifferential centrifugation and washed with assay buffer prior to use.The assay mixture contained 25 ul of BSA (40 mg/ml), 30 ul of rat livermicrosome solution (100 ug microsomal protein), 20 ul of assay buffer(0.1M K₂ PO₄, 1.0 mM reduced Glutathione, pH 7.4), 20 ug of cholesterolin 100 ul of a 0.6% Triton WR-1339 solution in assay buffer, and 5 ul oftest compound dissolved in 100% DMSO (total volume=180 ul). The assaymixture was incubated for 30 min at 37° C. The reaction was started bythe addition of 20 ul of 14° C.-Oleoyl-CoA (1000 uM, 2,000 dpm/nmol) andrun for 15 min at 37° C. The reaction was stopped by the addition of 1ml ETOH. The lipids were extracted into 4 ml hexane. A 3 ml aliquot wasdried under N₂, and resuspended in 100 ul of chloroform. 50 ul ofchloroform were spotted on a heat activated TLC plate and developed inhexane: diethyl ether: acetic acid (85:15:1, v:v:v). Incorporation ofradioactivity into cholesteryl esters was quantified on a BertholdLB2842 Linear TLC Analyzer. ACAT inhibition was calculated relative to aDMSO control assay.

The activity of the compounds of formula I in inhibiting intestinalabsorbtion of cholesterol may be determined by the procedure of Melchoirand Hatwell, J. Lipid. Res., 26, 306-315 (1985).

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹ H NMR) and C¹³ nuclearmagnetic resonance spectra (C¹³ NMR) were measured for solutions indeuterochoroform (CDCl₃) and peak positions are expressed in parts permillion (ppm) downfield from tetramethylsilane (TMS). The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; br, broad; c, complex.

EXAMPLE 1 Ethyl 2-(4-n-Propylphenylthio)nonanoate

1.6 g (0.033 mole) sodium hydride (50% dispersion in mineral oil) wasadded to a solution of 5.0 g (0.033 mole) 4-propylthiophenol in 25 mlanhydrous dimethylformamide. After 15 minutes, 8.8 g (0.033 mole) ethyl2-bromononanoate (prepared according to J. Labelled CompoundsRadiopharm. 14, 713 (1978)) was added and the resulting mixture wasstirred at room temperature overnight. The reaction mixture was thendiluted with 150 ml ethyl acetate and the resulting mixture was washedwith 5--60 ml water and then with 60 ml saturated aqueous sodiumchloride solution. The ethyl acetate solution was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The resulting oilwas chromatographed on 600 g silica gel, eluting with 7:3hexane/methylene chloride to yield 9.0 g (81% yield) of the desiredproduct as an oil.

¹ H NMR(CDCl₃): 0.88δ (c,6H); 1.1-1.5 (c,total 12H) including 1.12 (t,3H); 1.54-1.93 (c, 4H); 2.54 (t, 2H); 3.56 (q, 1H); 4.07 (q, 2H); 7.1(d, 2H); 7.36 (d, 2H).

EXAMPLE 1A 2-Hexylthiodecanoic Acid

17.3 g (0.36 mol) sodium hydride (50% dispersion in mineral oil) wasadded portionwise with stirring (gas evolution) to a solution of 26.8ml. (0.19 mol) hexanethiol in 500 ml. anhydrous dimethylformamide. Themixture was stirred at room temperature for 30 min., then 45.2 g (0.18mol) 2-bromodecanoic acid was added dropwise with stirring, keeping thetemperature of the reaction mixture below 45° C. The reaction mixturewas stirred at room temperature under nitrogen overnight. The mixturewas then diluted with 500 ml. water and the pH of the resulting mixturewas adjusted to 1.5 with 6N aqueous hydrochloric acid solution. Thismixture was extracted with 3×400 ml. ethyl acetate and the combinedethyl acetate extracts were washed with 5×700 ml. water and 1×500 ml.brine. The ethyl acetate solution was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The resulting oil waschromatographed on 2 kg. silica gel, eluting with methylene chloride toyield 35 g (67% yield) of the desired product as an oil.

EXAMPLE 1B Resolution of 2-hexylthiodecanoic acid

2-Hexylthiodecanoyl chloride was prepared by the procedure of Example4A. A solution of 2-hexylthiodecanoyl chloride (2.39 g., 7.8 mmol) in 20ml methylene chloride was added slowly with stirring under nitrogen to asolution of (R)-(-)-2-phenylglycinol (1.08 g, 7.9 mmol) and4-dimethylaminopyridine (0.96 g, 7.9 mmol) in 80 ml methylene chlorideat 5° C. The reaction mixture was stirred at room temperature overnight.Methylene chloride (100 ml.) was then added and the resulting solutionwas washed sequentially with 100 ml 1N aqueous hydrochloric acidsolution, 100 ml water, 100 ml saturated aqueous sodium bicarbonatesolution and 100 ml brine. The organic phase was dried over anhydroussodium sulfate and concentrated in vacuo to a solid residue (3.1 g). Thediastereomers were separated by column chromatography on 800 g silicagel using 1:1 hexane-diethyl ether as eluant. The less polardiastereomer (1.09 g, [α]_(D) ^(RT) =-9.85 (CH₃ OH); mp 98°-100° C.) and0.99 g of the more polar diastereomer ([α]_(D) ^(RT) =-9.46(CH₃ OH); mp105°-108° C.) were obtained along with 0.36 g of a mixture ofdiastereomers (total yield 76%). A solution of the less polardiastereomer (900 mg, 2.2 mmol) in 42 ml 1,4-dioxane and 42 ml 6Naqueous sulfuric acid solution was heated at 105° C. under nitrogen for15 hours. The reaction mixture was cooled to room temperature, dilutedwith 80 ml water and the resulting mixture was extracted with 4×60 mlethyl acetate. The combined ethyl acetate extracts were washed with 60ml brine, dried over anhydrous sodium sulfate and concentrated in vacuoto yield (S)-(-)-2-hexylthiodecanoic acid as an oil (634 mg., 99.6%yield); [α]_(D) ^(RT) =-59.5 (CH₃ OH).

In a similar manner, hydrolysis of the more polar diastereomer yielded98.4% of (R)-(+)-2-hexylthiodecanoic acid as an oil; [α]_(D) ^(RT)=+54.0(CH₃ OH).

EXAMPLE 2 Ethyl 2-(4-t-Butylphenylthio)octanoate

A mixture of 5.0 g (0.02 mole) ethyl 2-bromooctanoate, 3.37 g (0.02mole) p-t-butylthiophenol and 3.31 g (0.24 mole) potassium carbonate in70 ml acetone was refluxed under nitrogen overnight. The reactionmixture was cooled to room temperature and filtered and the filtrate wasconcentrated in vacuo. The residue was chromatographed on 500 g silicagel, eluting with 6:4 methylene chloride/hexane to yield 3.8 g (57%yield) of the desired product as an oil.

¹ H NMR(CDCl₃): δ 0.88 (c,3H); 1.1-1.52 (c,total 20H) including 1.14 (t,3H) and 1.3 (s); 1.66-2.11 (c, 2H); 358 (q, 1H); 4.1 (q, 2H); 7.36 (m,4H) .

EXAMPLE 3 2-(4-n-propylphenylthio)nonanoic acid

A solution containing 5.7 (0.017 mole) of the title compound of Example1, 35 ml of 1N aqueous sodium hydroxide solution (0.035 mole) and 3 mlmethanol was refluxed overnight. The resulting solution was cooled toroom temperature, acidified to pH 1.5 with 2N aqueous hydrochloric acidand extracted with 3×50 ml ethyl acetate. The combined ethyl acetateextracts were washed with 50 ml water and 50 ml saturated aqueous sodiumchloride solution, dried over anhydrous sodium sulfate and concentratedin vacuo to yield the title compound as an oil (5.0 g, 96% yield) whichwas used in the subsequent reaction without further purification.

¹ H NMR(CDCl₂): δ 0.88 (c, 6H); 1.17-1.54 (c, 12H); 1.54-1.92 (c, 4H);2.53 (t, 2H); 3.54 (t, 1H); 7.1 (d, 2H); 7,37 (d, 2H).

EXAMPLE 4 2-(4-n-Propylphenylthio)-N-(2,4,6-trimethoxyphenyl)nonanamide

1.54 g (5 Mole) of the title compound of Example 3 in 20 ml of thionylchloride was refluxed for 3 hours and then concentrated to dryness invacuo. 523 mg (1.6 mmole) of the resulting acid chloride was dissolvedin 20 ml methylene chloride and to the solution was added 292 mg (1.6mmole) 2,4,6-trimethoxyaniline and 195 mg (1.6 mmole)4-dimethylaminopyridine. The resulting solution was stirred at roomtemperature overnight and then concentrated in vacuo. The residue waspartitioned between 60 ml ethyl acetate and 20 ml 1N aqueoushydrochloric acid solution. The ethyl acetate layer was washed with 50ml water and 50 ml saturated aqueous sodium chloride solution, driedover anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct was chromatographed on 100 g silica gel, eluting with 1:1hexane/ethyl acetate to yield 370 mg (49% yield) of the title compoundas a whitish solid.

EXAMPLE 4 AN-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2-hexylthiodecanoic amide

A solution of 6.49 g (22.5 mmol) 2-hexylthiodecanoic acid in 40 mlthionyl chloride and 100 ml benzene was refluxed under nitrogen for 2.5hours and then concentrated to dryness in vacuo. The resulting acidchloride (6.88 g, 22.5 mmol) was dissolved in 15 ml. methylene chlorideand the solution was added dropwise to a solution of 4.63 g (23 mmol)5-amino4,6-bis(methylthio)-2-methylpyrimidine in 140 ml methylenechloride. The resulting solution was refluxed under nitrogen overnight.The reaction solution was then cooled, diluted with 140 ml methylenechloride and washed with 2×125 ml 3N aqueous hydrochloric acid solution,1×125 ml water, 1×125 ml saturated aqueous sodium bicarbonate solutionand 1×125 ml brine. The methylene chloride solution was dried overanhydrous sodium sulfate, filtered and concentrated to dryness in vacuo.The solid residue was recrystallized from diethyl ether yielding 5.35 gof the title compound, m.p. 99°-101° C. The filtrate was concentrated invacuo and the residue was chromato- graphed on 400 g silica gel elutingwith 9:1 hexane/ethyl acetate. Recrystallization of the product obtainedby chromatography from diethyl ether yielded another 2.32 g of the titlecompound, m.p. 99°-101° C. (total yield 72.4%).

¹ H NMR (CDCl₃): δ 0.87 (c, 6H); 1.21-1.84 (c, 21 H) , 2.02 (m, 1H);2.50 (s, 6H); 2.76 (s, 3H), 2.74 (t, 2H); 3.45 (t, 1H), 8.08 (s, 1H);

IR (CHCl₃): 2923, 2852, 1681, 1511, 1468, 1431, 1405 cm⁻¹.

EXAMPLE 4B N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hexylthiodecanoic amide

A solution of 4.19 g (13.7 mmol) 2-hexylthiodecanoyl chloride, preparedaccording to Example 4A, in 15 ml methylene chloride was added dropwisewith stirring under nitrogen to a solution of 2.75 g (13.7 mmol)3-amino-2,4-bis(methylthio)-6-methylpyridine in 30 ml pyridine cooled to5° C. The reaction mixture was stirred at room temperature undernitrogen overnight. Methylene chloride (250 ml) was then added to thereaction mixture and the resulting solution was washed with 3×50 ml 3Naqueous hydrochloric acid solution, 2×50 ml water, 1×50 ml saturatedaqueous sodium bicarbonate solution and 1×50 ml brine. The methylenechloride solution was dried over anhydrous sodium sulfate, filtered andconcentrated to dryness in vacuo. The solid residue (6.5 g) wasrecrystallized from petroleum ether to yield 4.7 g of the titlecompound, m.p. 75°-76.5° C. (72.8% yield).

¹ H NMR (CDCl₃): δ 0.86 (c, 6H); 1.16-1.74 (c, 21H); 2.04 (m, 1H); 2.4(s, 3H); 2.48 (s, 3H); 2.5 (s, 3H); 2.77 (t, 2H); 3.45 (t, 1H); 6.65 (s,1H); 8.14 (s, 1H).

IR (CHCl₃): 2922, 2852, 1676, 1600, 1561, 1466 cm⁻¹.

EXAMPLE 5 2-Bromo-N-(2,4,6-trimethoxyphenyl)decanamide

2-Bromodecanoic acid (1 g, 3.8 mmol) was heated under reflux in thionylchloride (10 ml) for 1 hour. The thionyl chloride was evaporated and theresidue was dissolved in dry ether (10 ml) and added dropwise to asolution of 2,4,6-trimethoxyaniline (0.7 g, 3.8 mmol) in pyridine (20ml) at 0° C. and the mixture was stirred for 1.5 hours. The reactionmixture was poured into saturated aqueous ammonium chloride andextracted three times with ethyl acetate (60 ml). The combined organicswere extracted with water and brine and dried and concentrated.Recrystallization from isopropyl ether afforded 1.1 g (65%) of the titlecompound, m.p. 109°-110° C. This material was used directly in the nextstep.

EXAMPLE 6 N-(2,4,6-Trimethoxy)phenyl-2-((2-pyridyl)thio)decanoamide

2-Thiopyridine (0.27 g, 2.4 mmol) in dimethylformamide (20 ml) wastreated with sodium hydride (0.1 g, 2.4 mmol, 60% oil dispersion) andstirred for 15 minutes at 25° C. To this cloudy solution, the titlecompound of Example 5 (1.0 g, 2.4 mmol) in dimethylformamide (10 ml) wasadded and the mixture and was stirred at 25° C. for 1.5 hours. Thereaction mixture was then poured into 1N HCl (75 ml) and extracted 3times with ethyl acetate (125 ml). The organics were dried, concentratedand chromatographed on silica gel (eluted with 1:1 ethylacetate:hexanes). Recrystallization from isopropyl ethyl afforded 0.4 g(36% ) of the title compound, m.p. 92° C.

¹ H NMR (CDCl₃): δ 8.52-8.42 (m, 2H), 7.54 (t, J=4 Hz, 1H), 7.26 (m,1H), 7.04 (t, J=4 Hz, 1H), 6.12 (s, 2H), 4.53 (t, J=3 Hz, 1H), 3.80(s3H), 3.66 (s, 6H), 2.26-0.86 (m, 17H). IR (CHCl₃): 2920, 1685, 1595cm⁻¹. Anal. Calculated for C₂₄ H₃₄ O₄ N₂ S: C, 64.55; H, 7.67; N, 6.27.Found: C, 64.34; H, 7.54; N, 6.20.

The title compounds of Examples 7 through 12 were prepared by aprocedure similar to that described in Example 4.

EXAMPLE 7 2-(4-t-Butylphenylthio)-N-[(2,4,6-trimethoxyphenyl)nonanamide(57% yield)

¹ H NMR: δ0.87 (c, 3H); 1.28 (s, 9H); 1.3 (c, 8H); 1.57 (c, 2H); 2.0 (c,2H); 3.70 (s, 6H); 3.78 (s+c, 4H); 6.11 (s, 2H); 7.29 (d, 2H); 7.42 (d,2H); 7.87 (s, 1H). IR (CHCl₃): 1672 cm⁻¹.

EXAMPLE 8 cl2-[4-(1,1-Dimethylpropyl)phenylthio]-N-(2,4,6-tri-methoxyphenyl]nonanamide(60% yield)

¹ H NMR:δ 0.65 (m, 3H); 0.87 (c, 3H); 1.24 (s, 6H); 1.28 (c, 8H); 1.62(c, 4H); 1.97 (c, 2H); 3.71 (s, 6H); 3.75 (m, 1H); 3.78 (s, 3H); 6.12(s, 2H); 7.22 (d, 2H); 7.41 (d, 2H); 7.89 (s, 1H). IR(CHCl₃): 1670 cm⁻¹.

EXAMPLE 9 2-(4-n-Butylphenylthio)-N-(2,4,6-trimethoxyphenyl)nonanamide(22% yield)

¹ H NMR: δ 0.89 (m, 6H); 1.32 (c, 10H); 1.58 (c, 4H); 1.97 (c, 2H); 2.55(m, 2H); 3.71 (s, 6H); 3.75 (m, 1H); 3.78 (s, 3H); 6.11 (s, 2H); 7.08(d, 2H); 7.41 (d, 2H); 7.86 (s, 1H). IR (CHCl₃): 1670 cm⁻¹.

EXAMPLE 10 2-[4-(1-Methylpropyl)phenoxy]-N-(2,4,6-trimethoxyphenyl)nonanamide (50% yield)

¹ H NMR: δ0.87 (c, 6H); 1.2 (d, 3H); 1.3 (c, 8H); 1.55 (m, 4H); 2.0 (m,2H); 2.55 (m, 1H); 3.70 (s, 6H); 3.77 (s, 3H); 4.6 (t, 1H); 6.1 (s, 2H);6.96 (d, 2H); 7.09 (d, 2H); 7.38 (s, 1H). IR (CHCl₃) 1680 cm⁻¹.

EXAMPLE 11 2-(4-n-Propylphenoxy)-N-(2,4,6-trimethoxyphenyl)-decanamide(59% yield)

¹ H NMR: δ 0.88 (c, 6H); 1.28 (c, 10H); 1.6 (c, 4H); 2.0 (m, 2H); 2.52(t, 2H); 3.71 (s, 6H); 3.77 (s, 3H); 4.59 (t, 1H); 6.1 (s, 2H); 6.95 (d,2H); 7.1 (d, 2H); 7.37 (s, 1H). IR (CHCl₃): 1683 cm¹.

EXAMPLE 12 2-(4-n-Propylphenylthio)-N- (2,4,6-trimethoxyphenyl)nonanamide (49% yield)

¹ H NMR:δ 0.89 (m, 6H); 1.3 (c, 8H); 1.59 (m, 4H); 1.95 (c, 2H); 2.53(t, 2H); 3.71 (s, 6H); 3.75 (m, 1H); 3.78 (s, 3H); 6.11 (s, 2H); 7.09(d, 2H); 7.41 (d, 2H); 7.86 (s, 1H). IR (CHCl₃): 1670 cm⁻¹.

The title compounds of Examples 13 through 24 were prepared by aprocedure similar to that described in Examples 5 and 6.

EXAMPLE 13 N-(2,4,6-Trimethyl)phenyl-2-(1-decylthio)octanamide

M.p. 42° C. ¹ H NMR:δ 8.06 (s, 1); 6.85 (s, 2); 3.39 (t, 3 Hz, 1); 2.61(t, 4 Hz, 2); 2.23 (s, 3); 2.16 (s, 6); 1.58 (m, 4); 1.23 (bs, 22); 0.84(t, 4 Hz, 6). IR (CHCl₃) 3340, 2930, 1675, 1500 cm⁻¹.

EXAMPLE 14 N-(2,4,6-Trimethyl)phenyl-2-((pyrid-2-yl)thio)decanamide

M.p. 85°-87° C. ¹ H NMR:δ 8.81 (s, 1); 8.36 (d, 2 Hz, 1); 7.50 (t, 3 Hz,1); 7.24 (d, 3 Hz, 1); 7.01 (t, 3 Hz, 1); 6.80 (s, 2); 4.48 (t, 3 Hz,1); 2.21 (s, 3); 2.0 (s, 6); 1.85-0.80 (m, 17). IR (CHCl₃) 2930, 1685,1585 cm⁻¹.

EXAMPLE 15 N-(2,4,6-Trimethyl)phenyl-2-((2-methylfuryl)thio) decanoamide

M.p. 64°-65° C. ¹ H NMR: δ 7.92 (bs, 1); 7.34 (s, 1); 6.88 (s, 2); 6.28(m, 1); 6.21 (d, 1 Hz, 1); 3.88 (s, 2); 3.42 (t, 3 Hz, 1); 2.26 (s, 3);2.18 (s, 6); 2.04-0.82 (m, 17). IR (CHCl₃): 2930, 1675, 1495 cm⁻¹.

EXAMPLE 16N-(2,4,6-Trimethyl)phenyl-2-[(2(6-ethoxy-benzothiazolyl)thio]octanamide

M.p. 106°-108° C. ¹ H NMR: δ 7.90 (s, 1); 7.60 (s, 1); 6.86 (s, 2); 4.83(t, 3 Hz, 1); 4.48 (t, 3 Hz, 1); 3.32 (q, 4 Hz, 2); 2.37 (s, 3); 2.12(s, 6) 2.0-0.85 (m, 26). IR (CHCl₃): 2920, 1680, 1595 cm⁻¹.

EXAMPLE 17N-(2,4,6-Trimethyl)phenyl-2-[4-(7-trifluoromethylquinolinyl)thio]decanamide

M.p. 195°-196° C. ¹ H NMR: δ 8.77 (d, 3 Hz, 1); 8.42 (s, 1); 8.27 (d, 5Hz, 1); 7.84 (s, 1); 7.77 (d, 5 Hz, 1); 8.54 (d, 3 Hz, 1); 6.80 (s, 2);4.26 (t, 3 Hz, 1); 2.22 (s, 3); 1.91 (s, 6); 2.20-0.80 (m, 17). IR(CHCl₃): 29,20, 1680, 1495 cm⁻¹.

EXAMPLE 18 N-(2,4,6-Trimethyl)phenyl-2-((2-thiazolyl)thio) decanamide

M.p. 74°-75° C. ¹ H NMR:δ 8.82 (bs, 1); 7.25 (d, 1 Hz, 1); 6.84 (s, 2);4.41 (t, 3 Hz, 1); 2.24 (s, 3); 2.05 (s, 6); 1.96-0.84 (m, 17). IR(CHCl₃ : 2920, 1850, 1685, 1490 cm⁻¹.

EXAMPLE 19 N-(2,4,6-Trimethyl)phenyl-2- ((2-quinolinyl)thio) decanamide

M.p. 11°-112° C. ¹ H NMR: δ 9.14 (bs, 1); 7.98 (d, 4 Hz, 1); 7.89 (d, 3Hz, 1); 7.77 (d, 3 Hz, 1); 7.65 (t, 3 Hz, 1); 7.47 (t, 3 Hz, 1); 7.31(d, 4 Hz, 1); 6.82 (s, 2); 4.82 (t, 3 Hz, 1) 2.38-0.85 (m, 28). IR(CHCl₃): 2920, 2850, 1680, 1590 cm⁻¹.

EXAMPLE 20 N-(2,4,6-Trimethoxy)phenyl-2-(1-hexylthio) octanamide

M.p. 56°-58° C. ¹ H NMR: δ 7.79 (s, 1); 6.12 (s, 2); 3.78 (s, 3); 3.76(s, 76 (s, 6); 3.44 (t, 4 Hz, 1); 2.66 (m, 2); 1.90-0.87 (m, 24). IR(CHCl₃): 2930, 1675, 1490 cm⁻¹.

EXAMPLE 21 N-(2,4,6-Trimethoxy)phenyl-2-(1-decylthio) octanamide

M.p. 54°-56° C. ¹ H NMR: δ (CDCl₃) 7.81 (s, 1); 6.15 (s, 2); 3.81 (s,3); 3.79 (s, 6); 3.47 (t, 4 Hz, 1) 2.69 (m, 4); 1.63-1.92 (m, 6); 1.60(m, 20); 0.90 (m, 6). IR (CHCl₃) 2920, 1670, 1600, 1460 cm⁻¹.

EXAMPLE 22 N-(2,4,6-Trimethyl)phenyl-2-(iso-butylthio) octanamide

M.p. 58°-60° C. ¹ H NMR:δ 8.03 (s, 1); 6.85 (s, 2) 3.37 (t, 4 Hz, 1);2.52 (m, 2); 2.17 (s, 6); 1.83-0.86 (m, 16). IR (CHCl₃): 2930, 1670,1495 cm⁻¹.

EXAMPLE 23 N-(2,4,6-Trimethyl)phenyl-2-[2-(3-propyloxypyridyl)thio]decanamide

M.p. 68°-69° C. ¹ H NMR: δ 8.74 (bs, 1); 8.02 (m, 1); 7.02 (d, 1 Hz, 2);6.82 (s, 2); 4.56 (t, 3 Hz, 1); 4.03 (t, 3Hz, 2); 2.25 (s, 3); 2.02 (s,6); 1.94-0.82 (m, 22). IR (CHCl₃): 2910, 2840, 1680, 1490 cm⁻¹.

EXAMPLE 24 N-(Isoquinolin-5-yl)-2-((2-pyridyl)thio) decanamide

M.p. 81°-83° C. ¹ H NMR: δ 9.24 (bs, 1); 8.60-8.36 (m, 3); 7.78-7.11 (m,7); 4.53 (t, 3 Hz, 1); (CHCl₃): 2940, 2860, 1700, 1590 cm⁻¹.

EXAMPLE 25N-(2,4,6-Trimethoxyphenyl)-2-methyl-2-(4-(1-methylpropyl)phenoxy)nonanoic amide

By use of the procedures described in Examples 1 and 3, ethyl2-bromononanoate and 4-(1-methylpropyl )phenol were coupled and theproduct saponified to give 2- (4-(1-methylpropyl)phenoxy)nonanoic acid.This material (1.0 g) was then methylated at the 2-position according tothe procedure of Pfeffer, et. al. (J. Org. Chem., 1972, 37, 451) to give2-methyl-2-hexanethiodecanoic acid (0.928 g). This material (0.86 g) wasconverted to the corresponding acid chloride with oxalyl chloride andcoupled with 2,4,6-trimethoxyaniline (0.49 g) according to the procedureof Adams and Ulrich (J. Am. Chem. Soc., 1920, 42, 599) to give the titlecompound (1.12 g).

Oil. ¹ H NMR: δ 7.82 (s, 1H); 7.12 (d, 6 Hz, 2 H); 7.07 (d, 6 Hz, 2 H);6.19 (s, 2 H); 3.85 (s, 3 H); 3.83 (s, 6 H); 2.61 (dt, 8 Hz, 1 H); 1.98(m, 2 H); 1.68-1.20 (m, 12 H); 1.52 (s, 3 H); 1.26 (d, 8 Hz, 3 H); 0.93(m, 3 H); 0.85 (t, 8 Hz, 3 H). ¹³ C NMR: δ 173.38, 159.90, 156.48,152.69, 142.12, 127.39, 121.24, 107.15, 91.02, 84.41, 55.83, 55.47,40.94, 40.06, 31.86, 31.32, 29.85, 29.33, 23.46, 22.68, 21.90, 21.67,14.11, 12.21. IR (CHCl₃) cm⁻¹ : 3410, 2940, 2850, 1680, 1608. Massspectrum m/e (relative intensity): M+485.42 (16), 336.28 (33), 308.28(24), 275.30 (30), 209.04 (40), 183.14 (100). High resolution massspectra: m.e 485.3134, calcd for C₂₉ H₄₃ NO₅ : 485.3141. Anal.: Calc'dfor C₂₉ H₄₃ NO₅ : C, 71.72; H, 8.93; N, 2.88. Found: C, 71.28; H, 8.87;N, 2.74.

EXAMPLE 26 N-(Isoquinolin-5-yl)-2-(4-(1-methylpropyl)phenoxy)nonanoicamide

N-(isoquinolin-5-yl)-2-bromodecanoic amide, prepared according to theprocedures described in Example 3 and 25, was coupled with4-(1-methylpropyl)phenol according to the procedure described in Example6 to give the title compound.

Oil. ¹ H NMR: δ 9.23 (s, 1 H); 8.61 (s, 1 H); 8.40 (d, 6 Hz, 1 H); 8.25(d, 6 Hz, 1 H); 7.80 (d, 9 Hz, 1H) 7.62 (dd, 6 and 9 Hz, 1 H); 7.19 (d,8 Hz, 2 H); 7.00 (d, 8 Hz, 2 H); 6.80 (d, 9 Hz, 1 H); 4.78 (t, 6 Hz, 1H); 2.58 (tq, 6 & 9 Hz, 1 H); 2.12 (m, 2 H); 1.60 (m, 4 H); 1.25 (m, 11H); 0.86 (t, 9 Hz, 3 H); 0.85 (t, 8 Hz, 3 H); ¹³ C NMR:δ 170.91, 155.34,154.48, 152.94, 143.20, 142.07, 130.83, 129.60, 129.02, 128.58, 128.01,127.40, 125.17, 124.26, 115.25, 113.49, 79.49, 40.94, 33.36, 31.80,31.30, 29.35, 29.16, 25.26, 22.67, 22.08, 14.13, 12.20.

IR (CHCl₃) cm⁻¹ : 3670, 3404, 2951, 2924, 1690, 1608, 1591. Massspectrum m/e (relative intensity): M+432.2 (16), 403.2 (7), 284.2 (30),255.2 (36), 171.1 (25), 144.1 (100). Anal.: Calc'd for C₂₈ H₃₆ N₂ O₂ :C, 77.74; H, 8.39; N, 6.48. Found: C, 76.12; H, 8.57; N, 5.03.

EXAMPLE 27 N-(Isoquinolin-5-yl)-2-(4-propylphenoxy)decanoic amide

N-(isoquinolin-5-yl)-2-bromodecanoic amide, prepared according to theprocedures described in Examples 3 and 25, was coupled with4-propylphenol according to the procedure described in Example 6 to givethe title compound.

Oil. ¹ H NMR: δ 9.24 (s, 1 H); 8.63 (s, 1 H); 8.41 (d, 5 Hz, 1 H); 8.24(d, 7 Hz, 1 H); 7.80 (d, 8 Hz, 1 H); 7.60 (dd, 6 & 6 Hz, 1 H); 7.21 (d,5 Hz, 1 H); 7.15 (d, 6 Hz, 2 Hz, H); 6.99 (d, 6 Hz, 2 H); 4.76 (t, 5 Hz,1 H); 2.55 (t, 6 2 H); 2.10 (m, 2 H); 1.62 (m, 4 H); 1.45-1.18 (br. m,10 H); 0.94 (t, 5 Hz, 3 H); 0.85 (t, 4 Hz, 3 H). ¹³ C NMR:δ 170.77,155.29, 153.01, 143.39, 136.99, 130.80, 129.94, 129.70, 129.00, 127.26,125.02, 123.96, 115.24, 113.27, 79.54, 37.12, 33.28, 31.82, 29.38,29.33, 29.19, 25.17, 24.70, 22.64, 14.08, 13.73. IR (CHCl₃) cm⁻¹ : 3397,2922, 1691, 1590. Mass spectrum m/e (relative intensity): M+432.30 (4),298.16 (24), 269.20 (36), 171.06 (22), 144.06 (100). Anal: Calc'd forC₂₈ H₃₆ N₂ O₂ : C, 77.74; H, 8.39; N, 6.48. Found: C, 77.63; H, 8.43; N,6.22.

EXAMPLE 28N-(Isoquinolin-5-yl)-N'-(4-(3-methylbutyl)phenylmethyl-N'-heptylurea

N-(4-(3-methylbutyl)phenyl)methyl-N-heptylamine was prepared and coupledwith commercially available 5-aminoisoquinoline according to theprocedure of DeVries, et. al. (J. Med. Chem., 29, 1131 (1986)) to givethe title compound.

Oil. ¹ H NMR: δ 9.15 (s, 1 H); 8.24 (d, 6 Hz, 1 H); 8.05 (d, 8 Hz, 1 H);7.65 (d, 8 Hz, 1 H); 7.50 (dd, 8 & 8 Hz, 1 H); 7.32 (d, 8 Hz, 2 H); 7.28(d, 8 Hz, 2 H); 6.67 (s, 1 H); 6.62 (d, 6 Hz, 1 H); 4.64 (s, 2 H); 3.52(t, 6 Hz, 2 H); 2.70 (t, 6 Hz, 2 H); 1.75 (m, 2 H); 1.67-1.20 (m, 11 H);0.95 (d, 6 Hz, 6 H); 0.88 (t, 6 Hz, 3 H). ¹³ C NMR: δ 155.72, 153.01,143.51, 142.73, 134.38, 133.42, 129.46, 129.35, 129.07, 127.40, 126.91,123.20, 123.02, 113.44, 51.34, 49.14, 41.03, 33.51, 31.87, 29.18, 28.79,27.79, 27.08, 22.66, 22.59, 14.14. IR (CHCl₃) cm⁻¹ : 3414, 2921, 2854,1662, 1591, 1507. Mass spectrum m/e (relative intensity): M+ 445.3 (6),304.0 (7), 274.2 (2), 190.1 (20), 170.0 (32), 161.2 (100). Highresolution mass spectra: m/e 445.3076, calc'd for C₂₉ H₃₉ N₃ O:445.3093. Anal.: Calc'd for C₂₉ H₃₉ N₃ O: C, 78.12; H, 8.82; N, 9.43.Found: C, 75.42; H, 8.59; N, 8.85.

EXAMPLE 29 N-(Isoquinolin-5-yl)-2-(methoxycarbonylmethyl)nonadecanoicamide

Commercially available N-(isoquinolin-5-yl)-2-(carboxymethyl)nonadecanoic amide was esterified with diazomethanein ether to give the title compound.

¹ H NMR: δ 9.16 (s, 1H); 8.57 (s, 1 H); 8.48 (d, 6 Hz, 1 H); 8.08 (d, 6Hz, 1 H); 7.70 (d, 8 Hz, 1 H); 7.66 (d, 8 Hz, 1 H); 7.50 (dd, 6 and 8Hz, 1 H); 5.50 (m, 1 H); 5.32 (m, 1 H); 3.70 (s, 3 H); 3.18-2.80 (m, 2H); 2.70-2.20 (m, 3 H); 1.95 (m, 2 H); 1.20 (m, 22 H); 0.85 (t, 6 Hz, 3H); ¹³ C NMR: δ 175.77, 170.66, 152.56, 142.68, 134.59, 134.39, 131.97,128.87, 127.84, 125.35, 124.78, 114.77, 114.60, 51/93, 43.32, 41.85,38.03, 35.28, 32.62, 32.54, 31.90, 29.68, 29.51, 29.43, 29.34, 29.19,22.67, 14.11.

IR (KBr) cm⁻¹ : 3418, 2918, 2848, 1724, 1692, 1591. Mass spectrum m/e(relative intensity): M+ 466.7 (1), 305.3 (2), 259.2 (11), 226.1 (76),186.1 (88), 171.0 (32) 144.0 (100).

Anal.: Calc'd for C₂₉ H₄₂ NO₃ : C, 74.96; H, 9.23; N, 5.83. Found: C,74.88; H, 9.27; N, 5.78.

EXAMPLE 30 N-(Isoquinolin-5-yl)-2-(decyl)cyclopentane carboxamide

2-(Decyl)cyclopentane carboxylic acid, prepared according to theprocedure of Hoefle, et. al. (U.S. Pat. No. 4,715,175), was coupled with5-aminoisoquinoline according to the procedure outlined in Example 47 togive the title compound.

¹ H NMR: δ 9.22 (s, 1 H); 8.51 (d, 5 Hz, 1 H); 8.10 (d, 7 Hz, 1 H); 7.78(d, 7 Hz, 1 H); 7.75 (s, 1 Hz, H); 7.59 (d, 7 Hz, 1 H); 7.52 (dd, 5 & 7Hz, 1 H); 2.26 (m, 2 H); 1.75 (m, 8 H); 1.23 (m, 16 H); 0.86 (t, Hz, 3H). ¹³ C NMR: δ 176.32, 153.13, 143.25, 131.98, 129.83, 129.04 127.304,124.70, 124.49 113.60, 55.70, 40.40, 36.23, 31.87, 30.18, 29.58, 29.49,20.30, 25.93, 24.74, 22.66, 14.09.

IR (KBr) cm⁻¹ : 3432, 2923, 2851, 1686, 1591, 1506. Mass spectrum m/e(relative intensity): M+ 381.28 (62), 240.08 (34), 209.20 (94), 144.08(100). Anal. Calc'd for C₂₅ H₃₆ N₂ O: C, 78.90; H, 9.54; N, 7.36. Found:C, 78.53; H, 9.58; N, 7.27.

EXAMPLE 31N-(3-Methylquinolin-5-yl)-2-(4-(1-methylpropyl)phenoxy)nonanoic amide

3-Methyl-4-chloro-5-nitroquinoline was hydrogenated using Pd/C to give3-methyl-5-aminoquinoline. This material was coupled with2-(4-(1-methylpropyl)phenoxy) nonanoic acid according to the procedureoutlined in Example 25 to give the title compound.

Oil. ¹ H NMR: δ 8.70 (s, 1 H); 8.48 (s, 1 H); 7.93 (d, 9 Hz, 1 H); 7.88(d, 9 Hz, 1 H); 7.64 (dd, 9 and 9 Hz, 1 H); 7.52 (s, 1 H); 7.18 (d, 9Hz, 2 H); 7.01 (d, 9 Hz, 2 H); 4.78 (dd, 6 & 8 Hz, 1 H); 2.61 (tq, 9 and9 Hz, 1 H); 2.40 (s, 3 H); 2.11 (m, 2 H); 1.72-1.26 (m, 12 H); 1.24 (d,7 Hz, 3 H); 0.90 (m, 3 H); 0.84 (t, 10 Hz, 3 H). ¹³ C NMR: δ 170.85,155.39, 152.24, 147.70, 141.84, 130.65, 128.50, 128.17, 128.07, 127.21,122.40, 121.62, 115.08, 79.43, 40.84, 33.39, 31.75, 31.31, 31.24, 29.32,29.13, 25.31, 22.62, 21.91, 18.87, 14.06, 12.20. Mass spectrum m/e(relative intensity): M+ 446.32 (11), 297.22 (59), 269.22 (85), 185.05(44), 158.08 (100). High resolution mass spectra: m/e 446.2938, calc'dfor C₂₉ H₃₈ N₂ O₂ : 446.2928. Anal.: Calc'd for C₂₉ H₃₈ N₂ O: C, 77.99;H, 8.58; N, 6.27. Found: C, 75.94; H, 8.40; N, 6.65.

EXAMPLE 32 N-(2-Methyl -6-fluoroquinolin-5-yl )-2-(hexylthio)decanoicamide

2-Methyl-5-amino-6-fluoroquinoline, prepared by reduction of thecorresponding nitro compound according to Example 31, was coupled with2-hexylthiodecanoic acid according to the procedure of Example 25 togive the title compound.

¹ H NMR: δ 8.52 (s, 1 H); 7.95 (d, 10 Hz, 1 H); 7.91 (m, 1H); 7.46 (dd,10 & 12 Hz, 1 H); 7.27 (d, 10 Hz, 1 H); 3.50 (t, 8 Hz, 1 H); 2.70 (s, 3H); 2.68 (t, 7 Hz, 1 H); 2.10 (m, 1 H); 1.82 (m, 1 H); 1.70-1.16 (m, 20H); 0.82 (t, 7 Hz, 6 H). ¹³ C NMR: δ 172,10, 158.50, 131.60, 129.80,122.72, 119.40, 119.20, 51.22, 33.07, 32.10, 31.82, 31.33, 29.36, 29.26,29.19, 28.59, 27.55, 25.10, 22.64, 22.49, 14.07, 13.97. IR (KBr) cm⁻¹ :3243, 2928, 2862, 1656. Mass spectrum m/e (relative intensity): M+446.34 (1), 243.20 (8), 231.14 (9), 218.10 (6), 176.14 (100). Anal.:Calc'd for C₂₆ H₃₉ FN₂ OS: C, 69,91; H, 8.80; N, 6.27. Found: C, 69.44;H, 8.82; N, 5.45.

EXAMPLE 33 N-(6-Methoxyquinolin-5-yl)-2-(hexylthio)decanoic amide

Commercially available 6-methoxyquinoline (13.80 g) was nitratedaccording to the procedure of Campbell, et. al. (J. Am. Chem. Soc.,1946, 68, 1559) to give 5-nitro-6-methoxyquinoline (17.51 g). This crudeproduct was directly reduced according to the procedure of Jacobs, et.al. (J. Am. Chem. Soc., 1920, 42, 2278) to give5-amino-6-methoxyquinoline (6.25 g). This material (0.45 g) was coupledwith 2-hexanethiodecanoic acid (0.75 g, prepared according to theprocedures described in Examples 1 and 3) using the procedure describedin Example 25 to give the title compound (0.63 g).

M.p. 88°-89° C. ¹ H NMR: δ 8.80 (d, 3 Hz, 1H); 8.59 (s, 1 H); 8.08 (d, 8Hz, 1 H); 8.02 (d, 7 Hz, 1 H); 7.51 (d, 8 Hz, 1 H); 7.36 (d, 3 & 7 Hz, 1H); 3.55 (t, 6 Hz, 1 H); 2.73 (t, 6 Hz, 2 H); 2.14-1.21 (m, 22H); 0.89(t, 6 Hz, 6 H). NMR: δ 172.10, 151.50, 148.50, 143.90, 131.52, 129.93,126.00, 121.33, 118.30, 115.76, 56.37, 51.35, 33.23, 32.02, 31.86,31.43, 29.43, 29.25, 29.35, 28.71, 27.62, 22.67, 22.54, 14.02. IR (KBr)cm⁻¹ : 3233, 2920, 2849, 1659, 1526, 1501. Mass spectrum m/e (relativeintensity): M+ 444.28 (4), 328.22 (9), 243.18 (14), 229.08 (14), 216.06(14), 174.20 (100). Anal.: Calc'd for C₂₆ H₄₀ N₂ O₂ S: C, 70.23; H,9.07; N, 6.30. Found: C, 70.05; H, 9.03; N, 6.23.

EXAMPLE 34 N-(6-methylthioquinolin-5-yl)-2-(hexylthio)decanoic amide

Commercially available 6-chloroquinoline (33.3 g) was nitrated accordingto the procedure described in Example 33 to give5-nitro-6-chloroquinoline (20.36 g). This material (15 g) was allowed toreact with sodium methylthiolate according to the procedure of Massie(Iowa State Coll. J. Sci. 1946, 21, 41; CA 41:3044 g) to give5-nitro-6-methylthioquinoline (13.61 g). This material (3.70 g) wasreduced using iron (5.62 g) and hydrochloric acid (1.5 ml) in 50%aqueous ethanol (50 ml) to give 5-amino-6-methylthioquinoline (3.0 g).This material (3.0 g) was coupled with 2-hexanethiodecanoic acid (5.83g, prepared according to the procedures described in Examples 1 and 3)using the procedure described in Example 25, to give the title compound(3.8 g).

M.p. 91°-92° C. ¹ H NMR: δ 8.85 (d, 3 Hz, 1 H); 8.62 (s, 1 H); 8.05 (d,9 Hz, 1 H); 8.00 (d, 9 Hz, 1 H); 7.65 (d, 9 Hz, 1 H); 7.40 (dd, 3 & 9Hz, 1 H); 3.55 (t, 8 Hz, 1 H); 2.80 (t, 8 Hz, 2 H); 2.50 (s, 3 H);2.10-1.35 (m, 17 H) ; 0.91 (t, 9 Hz, 6 H). ¹³ C NMR: δ 172.00, 149.84,131.37, 129.61, 126.91, 121.76, 51.22, 33.16, 32.36, 31.91, 31.47,29.47, 29.34, 29.30, 28.69, 27.82, 22.73, 22.59, 15.77, 14.17, 14.08. IR(CHCl₃) cm⁻¹ : 3318, 2923, 2852, 1677, 1586, 1567. Mass spectrum m/e(relative intensity): M+ 460.2 (2), 413.2 (6), 344.2 (23), 295.2 (13),243.2 (16), 217.0 (70), 190.1 (100).

Anal.: Calc'd for C₂₆ H₄₀ N₂ OS₂ : C, 67.78; H, 8.75; N, 6.08. Found: C,68.27; H, 8.46; N, 5.85.

EXAMPLE 35N-(Quinolin-5-yl-N'-(4-(3-methylbutyl)phenylmethyl)-N'-heptylurea

5-Aminoquinoline was converted to the title compound according to theprocedure described in Example 28.

Oil. ¹ NMR: δ 8.80 (d, 4 Hz, 1 H); 7.82 (d, 9 Hz, 1 H); 7.65 (dd, 6 & 9Hz, 1 H); 7.61 (d, 6 Hz, 1 H); 7.48 (d, 9 Hz, 1 H); 7.26 (d, 6 Hz, 2 H);7.22 (d, 6 Hz, 2 H); 7.15 (dd, 4 & 9 Hz, 1 H); 6.66 (s, 1 H); 4.53 (s, 2H); 3.55 (t, 9 Hz, 2 H); 2.65 (t, 9 Hz, 2 H); 1.70 (m, 2 H); 1.60 (m, 3H); 1.32 (m, 8 H); 1.00 (d, 6 Hz, 6 H); 0.88 (t, 6 Hz, 3 H). ¹³ C NMR: δ156.03, 150.00, 148.69, 143.30, 134.54, 134.20, 129.89, 129.35, 129.31,128.94, 126.96, 125.91, 120.73, 120.46, 51.19, 48.95, 41.05, 33.51,31.87, 29.18, 28.75, 27.77, 27.06, 22.66, 22.60, 14.14. IR (CHCl₃) cm⁻¹: 3416, 2913, 2855, 1665, 1596, 1509. Mass spectrum m/e (relativeintensity): M+ 445.3 (4), 304.2 (6), 274.3 (7), 190.1 (8), 161.2 (100).High resolution mass spectra: m/e 445.3104, calc'd for C₂₉ H₃₉ N₃ O:445.3093. Anal.: Calc'd for C₂₉ H₃₉ N₃ O: C, 78.12; H, 8.82; N, 9.43.Found: C, 75.75; H, 8.55; N, 9.00.

EXAMPLE 36N-(6-Methoxyquinolin-5-yl)-N'-(4-(3-methylbutyl)phenylmethyl)-N'-heptylurea

5-Amino-6-methoxyquinoline, prepared as described in Example 33, wasconverted to the title compound according to the procedure described inExample 28.

M.p. 86°-87° C. ¹ NMR: δ 8.73 (d, 3 Hz, 1 H); 8.15 (d, 6 Hz,1 H); 7.94(d, 8 Hz, 1 H); 7.39 (d, 8 Hz, 1 H); 7.30 (m, 3 Hz, H); 7.22 (d, 6 Hz, 2H); 6.44 (s, 1 Hz, H); 4.62 (s, 2 Hz, H); 3.80 (s, 3 Hz, H); 3.43 (t, 9Hz, 2 H); 2.62 (t, 9 Hz, 2 H); 1.76-1.21 (m, 13 Hz, H); 0.95 (d, 6 Hz, 6H); 0.88 (t, 6 Hz, 3 H). ¹³ C NMR: δ 156.97, 149.90, 148.27, 143.74,142.49, 134.83, 132.39, 128.78, 128.09, 127.18, 126.12, 121.11, 120.80,115.49, 56.25, 50.72, 48.08, 40.91, 33.45, 31.82, 29.12, 28.61, 28.45,27.70, 26.96, 22.58, 22.54, 14.09. IR (CHCl₃ cm⁻¹ : 3395, 2953, 2924,1651, 1504. Mass spectrum m/e (relative intensity): M+ 475.4 (6), 334.3(11), 200.1 (14), 173.1 (17), 161.2 (100). Anal.: Calc'd for C₃₆ H₄₁ N₃O₂ : C, 75.75; H, 8.69; N, 8.83. Found: C, 75.58; H, 8.90; N, 8.68.

EXAMPLE 37N-(7-Methoxyisoquinolin-8-yl)-2-(4-(1-methylpropyl)phenoxy)nonanoicamide

7-Methoxy-8-aminoquinoline, prepared by reduction of the correspondingnitro compound according to Example 31, was coupled with2-(4-(1-methylpropyl)phenoxynonanoic acid according to the procedure ofExample 25 to give the title compound.

Oil. ¹ H NMR: δ 9.14 (s, 1 H); 8.39 (d, 5 Hz, 1 H); 8.12 (s, 1 H); 7.73(d, 7 Hz, 1 H); 7.54 (d, 5 Hz, 1 H); 7.44 (d, 7 Hz, 1 H); 7.16 (d, 6 Hz,2 H); 7.01 (d, 6 Hz, 2 H); 4.74 (t, 5 Hz, 1 H); 3.79 (s, 3 H); 2.61 (tq,10 and 10 Hz, 1 H); 2.14 (m, 2 H); 1.58 (m, 4 H); 1.46-1.22 (br, m, 8H); 1.20 (d, 5 Hz, 3 H); 0.86 (m, 6 H). ¹³ C NMR: δ 172.16, 155.80,151.89, 148.40, 141.53, 140.95, 131.04, 128.19, 127.30, 125.60, 119.96,118.70, 115.40, 115.20, 79.93, 56.38, 40.89, 33.66, 31.79, 31.27, 29.38,29.19, 25.36, 22.64, 22.00, 14.09, 12.25. IR (CHCl₃) cm⁻¹ : Massspectrum m/e (relative intensity): M+ 462.30 (6), 314.22 (100), 285.22(50), 229.12 (59).

EXAMPLE 38N-(2-phenyl-4-methoxycarbonylquinolin-3-yl)-2-(4-(1-methylpropyl)phenoxy)nonanoicamide

2-phenyl-4-methoxycarbonylquinolin-3-ylquinoline was coupled with2-(4-(1-methylpropyl )phenoxynonanoic acid according to Example 25 togive the title compound.

M.p. 89°-91° C. ¹ H NMR: δ 8.56 (s, 1 H); 8.14 (d, 9 Hz, 1 H); 8.05 (d,Hz, 1 H); 7.71 (dd, 7 and 7 Hz, 1 H); 7.58 (dd, 7 & 7 Hz, 1 H); 7.52 (d,7 Hz, 2 H); 7.36 (m, 3 H); 7.07 (d, 8 Hz, 2 H); 6.69 (d, 8 Hz, 2 H);4.41 (t, 6 Hz, 1 H); 3.89 (s, 3 H); 2.55 (tq, 7 and 7 Hz, 1 H); 1.74 (m,2 H); 1.58 (m, 2 H); 1.10-1.40 (br, m, 10 H); 0.84 (m, 6 H). ¹³ C NMR: δ170.78, 166.20, 155.56, 146.30, 141.51, 138.40, 132.60, 129.90, 129.66,128.96, 128.68, 128.61, 128.17, 127.95, 124.95, 123.81, 121.70, 115.18,52.76, 40.87, 32.93, 31.73, 31.25, 29.04, 25.03, 22.61, 22.01, 14.08,12.24. IR (CHCl₃) cm⁻¹ : 3410, 2960, 1725, 1680, 1620. Mass spectrum m/e(relative intensity): M+ 566.36 (13), 417.24 (29), 389.26 (23), 357.22(13), 205.12 (45), 279.12 (100). Anal.: Calc'd for C₃₆ H₄₂ N₂ O₄ : C,76.30; H, 7.47; N, 4.94. Found: C, 76.01; H, 7.55; N, 4.91.

EXAMPLE 39N-(3-Methoxypyridin-2-yl)-2-(4-(1-methylpropyl)phenoxy)nonanoic amide

3-Methoxy-2-aminopyridine, prepared by reduction of the correspondingnitro compound according to Example 31, was coupled with2-(4-(1-methylpropyl)phenoxynonanoic acid according to Example 25 togive the title compound.

Oil. ¹ H NMR: δ 8.90 (s, 1 H); 8.05 (d, 3 Hz, 1 H); 7.25 (m, 3 H); 6.97(d, 3 Hz, 1 H) ; 6.89 (d, 9 Hz, 2 H); 4.64 (t, 7 Hz, 1 H); 3.74 (s, 3H); 2.50 (tq, 12 & 12 Hz, 1 H); 1.98 (m, 2 H); 1.51 (m, 4 H); 1.18-1.08(br, m, 11 H); 0.84 (t, 4 Hz, 3H); 0.76 (t, 5 Hz, 3 H). ¹³ C NMR: δ172.40, 156.00, 140.10, 128.15, 119.86, 117.34, 115.45, 55.68, 40.84,33.20, 32.30, 31.75, 31.24, 29.34, 29.11, 27.60, 25.26, 22.61, 21.70,14.06, 12.19. IR (CHCl₃) cm⁻¹ : 3387, 2922, 2854, 1702, 15.98. Massspectrum m/e (relative intensity): M+ 412.34 (8), 313.22 (41), 263.22(100), 151.08 (30). Anal.: Calc'd for C₂₅ H₃₆ N₂ O₃ : C, 72.78; H, 8.80;N, 6.80. Found: C, 71.49, H, 8.88; N, 6.03.

EXAMPLE 40N-(2-Methoxy-4-methylpyridin-2-yl)-2-(4-(1-methylpropyl)phenoxy)nonanoicamide

3-Nitro-4-methyl-2-pyridone was methylated with methyl iodide andreduced with zinc and acetic acid to give2-methoxy-3-amino-4-methylpyridine. This material was coupled with2-(4-(1-methylpropyl )phenoxynonanoic acid according to the procedure ofExample 25 to give the title compound.

Oil. ¹ H NMR: δ 8.19 (s, 1 H); 7.10 (d, 7 Hz, 2 H); 7.04 (d, 5 Hz, 1 H);6.93 (d, 7 Hz, 2 H); 6.03 (d, 5 Hz, 1 H); 4.63 (t, 6 Hz, 1 H); 3.48 (s,3 H); 2.53 (tq, 11 & 11 Hz, 1 H); 2.07 (s, 3 H); 2.03 (m, 2 H); 1.55 (m,4 H); 1.28 (m, 8 H); 1.18 (d, 6 Hz, 3 H); 0.87 (m, 3 H); 0.79 (t, 5 Hz,3 H). ¹³ C NMR: δ 170.87, 159.58, 155.83, 143.55, 141.21, 133.70,128.08, 124.35, 115.47, 109.06, 40.84, 37.44, 33.37, 31.75, 31.28,31.25, 29.28, 29.07, 25.19, 22.61, 21.92, 19.47, 14.08, 12.20. IR(CHCl₃) cm⁻¹ : 2920, 2852, 1685, 1655, 1606. Mass spectrum m/e (relativeintensity): M+ 426.32 (10), 327.16 (7), 277.20 (52), 249.20 (35), 165.18(100). Anal.: Calc'd for C₂₆ H₃₈ N₂ O₃ : C, 73.20; H, 8.98; N, 6.57.Found: C, 73.06; H, 9.11; N, 6.28.

EXAMPLE 41 N-(2-Methoxy-4-methylpyridin-2-yl)-2-(hexylthio)decanoicamide

3-Nitro-4-methyl-2-pyridone was methylated with methyl iodide andreduced with zinc and acetic acid to give2-methoxy-3-amino-4-methylpyridine. This material was coupled with2-hexylthiodecanoic acid according to the procedure of Example 25 togive the title compound.

M.p. 83°-85° C. ¹ H NMR: δ 8.55 (s, 1 H); 7.04 (d, 6 Hz, 1 H); 6.07 (d,6 Hz, 1 H); 3.54 (s, 3 H); 3.41 (t, 6 Hz, 1 H); 2.12 (s, 3 H); 2.03-1.17(br, m, 22 H); 0.84 (t, 5 Hz, 3 H). ¹³ C NMR: δ 171.36, 159.74, 142.90,133.40, 125.06, 109.20, 50.91, 37.47, 33.01, 31.82, 31.73, 31.38, 29.33,29.27, 29.25, 28.52, 27.55 22.66, 22.52, 19.51, 14.10, 14.03. IR (KBr)cm⁻¹ : 3232, 2920, 2850, 1652, 1592. Mass spectrum m/e (relativeintensity): M+ 408.38 (5), 292.30 (16), 193.12 (17), 165.10 (54), 138.22(100). Anal.: Calc'd for C₂₃ H₄₀ N₂ O₂ S: C, 67.60; H, 9.87; N, 6.86.Found: C, 67.56; H, 9.56; N, 6.58.

EXAMPLE 42N-(2-Methoxy-4-methylpyridin-2-yl)-N'-(4-(3-methylbutyl)phenylmethyl)-N'-heptylurea

3-Nitro-4-methyl-2-pyridone was methylated with methyl iodide andreduced with zinc and acetic acid to give2-methoxy-3-amino-4-methylpyridine. This material was converted to thetitle compound according to the procedure described in Example 28.

M.p. 90°-91° C. ¹ H NMR: δ 7.20 (d, 15 Hz, 2 H); 7.16 (d, 15 Hz, 2 H);6.95 (d, 6 Hz, 1 H); 6.82 (s, 1 H); 6.08 (d, 6 Hz, 1 H); 4.53 (s, 2 H);3.53 (s, 3 H); 3.31 (t, 6 Hz, 2 H); 2.58 (t, 6 Hz, 2 H); 2.15 (s, 3 H);1.70-1.43 (br, m, 8 H); 1.24 (m, 10 H); 0.90 (d, 5 Hz, 6 H); 0.86 (t, 4Hz, 3 H). NMR: δ 159.98, 155.75, 142.66, 140.27, 135.04, 131.35, 128.63,128.33, 128.07, 127.54, 127.32, 109.91, 53.87, 50.39, 49.55, 47.44,40.89, 40.81, 37.48, 33.43, 31.84, 31.78, 30.12, 29.25, 29.02, 28.17,27.66, 27.35, 26.99, 22.63, 22.54, 19.48, 14.09. IR (KBr) cm⁻¹ : 2952,2922, 1660, 1635, 1590. Mass spectrum m/e (relative intensity): M+439.40 (14), 298.26 (10), 274.30 (26), 190.20 (40), 165.08 (81), 161.14(100). Anal.: Calc'd for C₂₇ H₄₁ N₃ O₂ : C, 73.76; H, 9.40; N, 9.56.Found: C, 73.85; H, 9.25; N, 9.35.

EXAMPLE 43N-(Imidazo[1,2-a]pyridin-3-yl)-2-(4-(1-methylpropyl)phenoxy)nonanoicamide

3-Aminoimidazo[1,2-a]pyridine, synthesized by reduction of thecorresponding nitro compound according to Example 31, was coupled with2-(4-(1-methylpropyl)- phenoxynonanoic acid according to the procedureof Example 25 to give the title compound.

Oil. ¹ H NMR: δ 8.78 (s, 1 H); 7.72 (d, 6 Hz, 1 H); 7.62 (d, 8 Hz, 1 H);7.55 (s, 1 H); 7.24 (d, 9 Hz, 2 H); 7.20 (dd, 7 and 7 Hz, 1 H); 6.94 (d,9 Hz, 2 H) ; 6.85 (dd, 7 and 7 Hz, 1 H); 4.52 (t, 6 Hz, 1 H); 2.51 (tq,11 and 11 Hz, 1 H); 1.94 (m, 2 H); 1.50 (m, 4 H); 1.20-1.10 (br m, 11H); 0.90-0.70 (br. m, 6 H). ¹³ C NMR: 172.45, 156.14, 148.75, 144.99,140.63, 128.32, 127.90, 127.84, 121.41, 121.17, 120.89, 117.20 114.91,76.93, 61.03, 41.15, 34.43, 32.94, 31.23, 29.14, 28.69, 25.01, 22.66,21.93, 21.81, 14.16, 12.19. IR (KBr) cm⁻¹ : Mass spectrum m/e (relativeintensity): M+ 421.28 (25), 272.18 (51), 159.04 (58), 133.04 (100).Anal.: Calc'd for C₂₆ H₃₅ N₃ O₂ : C, 74.25; H, 8.39; N, 9.99. Found: C,73.82; H, 9.02; N, 9.56.

EXAMPLE 44 N-(Imidazo[1,2-a]pyridin-3-yl)-2-(hexylthio)decanoic amide

3-Aminoimidazo[1,2-a]pyridine, synthesized by reduction of thecorresponding nitro compound according to the procedure of Example 31,was coupled with 2-hexylthiodecanoic acid according to Example 25 togive the title compound.

¹ H NMR (CDCl₃): 8.66 (s, 1H); 7.75 (d, 5Hz, 1H); 7.62 (d, 8Hz, 1H);7.52 (s, 1H); 7.22 (dd, 7 & 8Hz, 1H); 6.84 (dd, 5 & 7Hz, 1H); 3.48 (t,6Hz, 1H); 2.67 (t, 6Hz, 2H); 2.03 (m, 1H); 1.83 (m, 1H); 1.70-1.15 (m,20H); 0.85 (m, 6H).

EXAMPLE 45 N-(8-Chloro-6-methoxyquinolin-5-yl )-2-hexylthiodecanoicamide

5-Amino-6-methoxy-8-chloroquinoline, produced as a side product of thereduction procedure described in Example 33, was coupled with2-hexylthiodecanoic acid according to the procedure described in Example25 to give the title compound.

Mp=110°-111° C. Anal.: Found: C, 65.40; H, 8.06; N, 5.73. Calc'd for C₂₆H₃₉ ClN₂ O₂ S: C, 65.18; H, 8.42; N, 5.85.

EXAMPLE 46 N-(6,8-Di/methylthio)quinolin-5-yl)-2-hexylthiodecanoic amide

5-Amino-6,8-di(methylthio)quinoline, produced as a side product of theprocedure described in Example 34, was coupled with 2-hexylthiodecanoicacid according to the procedure described Example 25 to the give titlecompound.

Mp=91°-93 ° C.

EXAMPLE 47 N-(6-Methylthioquinolin-5-yl)-2-(4-sec-butylphenoxy)nonanoicamide

5-Amino-6-methylthioquinoline, prepare as described in Example 34, wascoupled with 2-(4-sec-butylphenoxy)nonanoic acid according to theprocedure described in Example 25 to give the title compound.

Oil. Anal.: Found: C, 71.35; H, 7.98; N, 5.54. Calc'd. for C₂₉ H₃₈ N₂ O₂S: C, 72.76; H, 8.00; N, 5.85.

EXAMPLE 48N-(6-Methylthioquinolin-5-yl)-2-octanyl-1,3-dithiane-2-carboxamide

5-Amino-6-methylthioquinoline, prepared as described in Example 34, wascoupled with 2-octanyl-1,3-dithiane-2-carboxylic acid, prepared bytreatment of 1,3-dithiane-2-carboxylic acid withsodiumhexamethyldisilazide and octanyl bromide, according to Example 25to give the title compound.

Oil. Anal.: Found: C, 59.11; H, 5.81; N, 6.07. Calc'd. for C₂₃ H₃₂ N₂OS₃ : C, 61.57; H, 7.19; N, 6.24.

EXAMPLE 49 N-(6-ethoxyquinolin-5-yl)-2-hexylthiodecanoic amide

6-Hydroxyquinoline was treated with sodium hydride and ethyl iodide togive 6-ethoxyquinoline. This material was nitrated, reduced and coupledwith 2-hexylthiodecanoic acid according to the procedure of Example 33to give the title compound.

Mp=88°-90° C. Anal.: Found: C, 70.37; H, 9.01; N, 6.26. Calc'd. for C₂₇H₄₂ N₂ O₂ S: C, 70.69; H, 9.23; N, 6.11.

EXAMPLE 50 N-(6-fluoroquinolin-5-yl)-2-hexylthiodecanoic amide

6-Fluoroquinoline, prepared according to the procedure of Sveinbjornssonet. al. (J. Org. Chem., 1951, 16, 1450), was nitrated, reduced andcoupled with 2-hexylthiodecanoic acid according to the procedure ofExample 33 to give the title compound.

Mp=74°-75° C. Anal.: Found: C, 69.04; H, 8.55; N, 6.57. Calc'd. for C₂₅H₃₇ FN₂ OS: C, 69.40; H, 8.62; N, 6.48.

The title compounds of Examples 51-53 were prepared according to theprocedure described in Example 4.

EXAMPLE 514,5-Dimethyl-trans-2-n-heptyl-N-(2,4,6-trimethoxyphenyl)-cyclohex-4-enecarboxamide

72% yield. IR(CHCl₃): 1675 cm⁻¹. ¹ H NMR: δ 0.86 (t, 3H); 1.62 (s) and1.12-2.48 (c) (total 24H); 3.78 (s, 6H); 3.79 (s, 3H); 6.13 (s, 2H);6.48 (s, 1H).

EXAMPLE 524,5-Dimethyl-trans-2-n-nonyl-N-(2,4,6-trimethoxyphenyl)cyclohex-4-enecarboxamide

66% yield. IR(CHCl₃): 1676 cm⁻¹. ¹ H NMR: δ0.86 (t, 3H); 1.62 (s) and1.12-2.48 (c) (total 28 H); 3.78 (s, 6H); 3.79 (s, 3H); 6.13 (s, 2H);6.48 (s, 1H).

EXAMPLE 534,5-Dimethyl-trans-2-n-octyl-N-(2,4,6-trimethoxyphenyl)cyclohex-4-enecarboxamide

46% yield. IR(CHCl₃): 1676 cm⁻¹. ¹ H NMR: δ 0.86 (t, 3H); 1.62 (s) and1.12-2.48 (c) (total 26 H); 3.78 (s, 6H); 3.79 (s, 3H); 6.13 (s, 2H);6.48 (s, 1H).

Using the procedure described in Example 4, the amides in thebicyclo[2.2.1]hept-5-ene and bicyclo[2.2.2]oct-5-ene series of Examples54-59 were obtained as mixtures of endo and exoisomers which could beseparated by column chromatography on silica gel, eluting withhexane/ethyl acetate.

EXAMPLE 543-n-Nonyl-endo-N-(2,4,6-trimethoxyphenyl)-bicyclo[2.2.1]hept-5-ene-2-carboxamide

30% yield. IR(CHCl₃): 1663 cm⁻¹. ¹ H NMR: δ 0.86 (t, 3H); 1.15-1.62 (c,18H); 1.79 (c, 1H); 2.51 (c, 1H); 2.61 (c, 1H); 3.16 (c, 1H); 3.77 (s,6H); 3.78 (s, 3H); 6.11 (s) and 6.14 (c) (total 3H); 6.3 (c, 1H); 6.36(s, 1H).

EXAMPLE 55Endo-3-n-nonyl-exo-N-(2,4,6-trimethoxyphenyl)-bicyclo[2.2.1]hept-5-ene-2-carboxamide

26% yield. IR(CHCl₃): 1678 cm⁻¹. ¹ H NMR: δ 0.86 (t, 3H); 1.14-1.45 (c,17H); 1.66 (c, 1H); 1.91 (c, 1H); 2.4 (c, 1H); 2.8 (c, 1H); 3.0 (c, 1H);3.78 (s, 9H); 6.13 (s+c, 3H); 6.21 (c, 1H); 6.42 (s, 1H).

EXAMPLE 56Exo-3-n-octyl-endo-N-(2,4.6-trimethoxyphenyl)-bicyclo[2.2.2]oct-5-ene-2-carboxamide

20% yield. IR(CHCl₃): 1666 cm⁻¹. ¹ H NMR: δ 0.86 (t, 3H); 1.02-1.87 (c,19H); 2.11 (c, 1H); 2.45 (C, 1H); 2.84 (c, 1H); 3.76 (s, 6H); 3.78 (s,3H); 6.11 (s, 2H); 6.3 (c, 1H); 6.42 (s, 1H); 6.5 (c, 1H).

EXAMPLE 57 Endo-3-n-octyl-exo-N-(2,4,6-trimethoxyphenyl)bicyclo[2.2.2]oct-5-ene-2-carboxamide

24% yield. IR(CHCl₃): 1680 cm⁻¹. ¹ H NMR: δ0.86 (t, 3H); 1.06 (c, 1H);1.25 (c, 14H); 1.65 (c, 2H); 1.89 (c, 2H); 2.16 (c, 1H); 2.46 (c, 1H);2.78 (c, 1H); 3.77 (s, 6H); 3.79 (s, 3H); 6.13 (s, 2H); 6.21 (c, 1H);6.32 (c, 1H); 6.43 (s, 1H).

EXAMPLE 58Exo-2-n-nonyl-endo-N-(2,4,6-trimethoxyphenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

40% yield. IR(CHCl₃): 1677 cm⁻¹. ¹ H NMR: δ 0.86 (t, 3H); 1.27 (c, 12H);1.4-1.7 (c, 6H); 1.88 (c, 1H); 2.02 (c, 1H); 2.82 (c, 2H); 3.76 (s, 6H);3.77 (s, 3H); 6.12 (s, 2H); 6.2 (c, 2H); 6.4 (s, 1H).

EXAMPLE 59Endo-2-n-nonyl-exo-N-(2,4,6-trimethoxyphenyl)-bicyclo[2.2.1]hept-5-ene-2-carboxamide

2% yield. IR 1675 cm⁻¹. ¹ H NMR: δ 0.84 (t, 3H); 1.12-2.06 (c, 19H);2.45 (c, 1H); 2.82 (c, 1H); 3.17 (c, 1H); 3.77 (s, 6H); 3.79 (s, 3H);6.05-6.27 (c, 4H); 6.6 (s, 1H).

The title compounds of Examples 60-64 were prepared according to theprocedure described in Example 4.

EXAMPLE 60 2-n-Nonyl-N-(2,4,6-trimethoxyphenyl)indane-2-carboxamide

72% yield. IR(CHCl₃): 1676 cm⁻¹. ¹ H NMR:δ 0.86 (t, 3H); 1.24 (c, 12H);1.49 (c, 3H); 1.75 (c, 2H); 2.97 (d, 2H); 3.54 (d, 2H); 3.74 (s, 6H);3.78 (s,3H); 6.12 (s, 2H); 6.51 (s, 1H); 7.2 (c, 4H).

EXAMPLE 612-n-Octyl-N-(2,4,6-trifluorophenyl)-1,2,3,4-tetrahydro-2-naphthamide

22% yield. ¹ H NMR:δ 0.86 (t, 3H); 1.15-1.6 (c, 13H); 1.9 (c, 2H); 2.2(c, 1H); 2.88 (c, 3H); 3.27 (d, 1H); 6.66 (c, 3H); 7.13 (s, 4H).

EXAMPLE 622-n-Octyl-N-(2,4,6-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-naphthamide

65% yield. ¹ H NMR: δ 0.87 (t, 3H); 1.29 (c, 10H); 1.5 (c, 3H); 1.86 (C,2H); 2.22 (C, 1H); 2.8 (c, 2H); 3.0 (c, 1H); 3.3 (d, 1H); 3.66 (s, 6H);3.75 (s, 3H); 6.06 (s, 2H); 6.56 (s, 1H); 7.10 (s, 4H).

EXAMPLE 63 2-n-Decyl-N-(2,4,6-trimethophenyl)indane-2-carboxamide

61% yield. IR(CHCl₃) 1675 cm⁻¹.

¹ H NMR: δ 0.86 (t, 3H); 1.23 (c, 14H); 1.49 (c, 2H); 1.75 (c, 2H); 2.97(d, 2H); 3.54 (d, 2H); 3.74 (s, 6H); 3.78 (s, 3H); 6.12 (s, 2H); 6.5 (s,1H); 7.2 (c, 4H).

EXAMPLE 64 2-n-Decyl-N-(2,4,6-trifluorophenyl)indane-2-carboxamide

33% yield. IR(CHCl₃) 1695 cm⁻¹.

¹ H NMR: δ 0.86 (t, 3H); 1.23 (c, 14H); 1.42 (c, 2H); 1.78 (c, 2H); 3.02(d, 2H); 3.5 (d, 2H); 6.72 (c, 3H); 7.22 (c, 4H).

EXAMPLE 652-n-Nonyl-N-(2,4,6-trifluorophenyl)-1,2,3,4-tetrahydro-2-naphthamide

To a solution of 1.0 g (6.8 mmole) 2,4,6-trifluoroaniline and 830 mg(6.8 mmole) 4-dimethylaminopyridine in 40 ml methylene chloride cooledto 5° C. under nitrogen was added a solution of 2.12 g (6.6 mmole)2-n-nonyl-1,2,3,4-tetrahydro-2-naphthoyl chloride in 10 ml methylenechloride. The resulting solution was stirred at room temperature for 44hours. Fifty milliters of methylene chloride was then added and thesolution was washed sequentially with 30 ml aqueous hydrochloric acid,30 ml water and 30 ml brine. The methylene chloride solution was driedover anhydrous sodium sulfate and concentrated to dryness in vacuo. Theresidue (2.5 g) was purified by column chromatography on silica geleluting with 2:1 methylene chloride-hexane to yield 1.66 g (58% yield)of the desired product as a white, low melting solid.

IR(CHCl₃) 1691 cm¹. ¹ H NMR: δ 0.87 (t, 3H); 1.16-1.6 (c, 15H); 1.9 (c,2H); 2.2 (c, 1H); 2.9 (c, 3H); 3.27 (d, 1H); 6.67 (m, 2H); 6.73 (s, 1H);7.13 (s, 4H).

EXAMPLE 662-n-Nonyl-N-(2,4,6-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-naphthamide

The title compound was prepared according to the procedure described inExample 65, except that 422 mg 2-n-nonyl-1,2,3,4-tetrahydro-2-naphthoylchloride, 247 mg (1.3 mmole) 2,4,6-trimethoxyaniline, and 165 mg (1.3mmole) 4-dimethylaminopyridine in 12 ml methylene chloride were stirredat room temperature for 20 hours. There was obtained 421 mg product (68%yield). IR(CHCl₃) 1670 cm⁻¹. ¹ H NMR: δ 0.87 (t, 3H); 1.25 (c, 12H); 1.5(c, 3H); 1.85 (c, 2H); 2.21 (c, 1H); 2.8 (c, 2H); 3.0 (c, 1H); 3.3 (d,1H); 3.66 (s, 6H); 3.75 (s, 3H); 6.06 (s, 2H); 6.56 (s, 1H); 7.1 (s,4H).

EXAMPLE 67 2-n-Nonyl-N-(2,4,6-trifluorophenylindane-2 -carboxamide

The title compound was prepared according to the procedure described inExample 65, except that 398 mg (1.3 mmple) 2-n-nonylindane-2-carbonylchloride, 220 mg (1.5 mmole) 2,4,6-trifluoroaniline, and 187 mg (1.5mmole) 4-dimethylaminopyridine in 12 ml methylene chloride were stirredat room temperature for 44 hours. There was obtained 290 mg product. 54%yield. IR(CHCl₃): 1693 cm⁻¹. ¹ H NMR: δ 0.86 (t, 3H); 1.23 (c, 12H);1.41 (c, 2H); 1.78 (c, 2H); 3.02 (d, 2H); 3.5 (d, 2H); 6.7 (c, 3H); 7.18(c, 4H).

EXAMPLE 68N-(2,4,6-Trimethoxy)phenyl-2-[(2-(6-ethoxybenzthiazolyl)thio]octanamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p. 78°-81° C. ¹ H NMR (CDCl₃) 8.13 (s, 1); 7.69 (d, 4 Hz, 1); 7.22 (d,1 Hz, 1); 6.98 (dd, 1); 6.06 (s, 1); 4.65 (t, 4 Hz, 1); 4.07 (q, 3 Hz,2); 3.81 (s, 2); 3.76 (s, 2); 3.54 (s, 6); 2.2-1.2 (m, 12); 0.89 (m, 3).IR(CHCl₃) 3400, 2929, 1690, 1520 cm⁻¹.

EXAMPLE 69 N-(2,4,6-Trimethoxy)phenyl-2-((1-tert-nonyl)thio)octanamide.

The title compound was prepared according to the procedures described inExamples 5 and 6.

Oil. ¹ H NMR (CDCl₃) 8.10 (bs, 1); 3.82 (s, 3); 3.79 (s, 6); 3.40 (bs,1); 1.98-0.80 (m, 32). IR(CHCl₃) 3320, 2950, 1670, 1600 cm⁻¹.

EXAMPLE 70 N-(5-Isoquinolinyl)-2-((1-N-hexyl)thio)heptanamide

The title compound was prepared according to the procedures described inExamples 1 through 4.

M.p. 83°-85° C. ¹ H NMR (CDCl₃) 9.30 (bs, 1); 9.16 (s, 1); 8.48 (d, 4Hz, 1); 8.23 (d, 4 Hz, 1); 7.71-7.46 (m, 3); 3.47 (t, 2 Hz, 1); 2.58 (t,5 Hz, 2); 2.08-0.76 (m, 20). IR (CHCl₃) 3317, 2921, 1682, 1515 cm⁻¹.

EXAMPLE 71 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-hexyl)thio)decanoamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p. 55°-56° C. C, calc'd, 67.19; Found, 66.41. ¹ H NMR (CDCl₃) 67.81(bs, 1); 6.14 (s, 2); 3.81 (s, 3); 3.78 (s, 6); 3.48 (s, 6); 3.46 (t,Hz, 1); 2.69 (bs, 2); 1.98-0.76 (m, 28). IR (CHCl₃) 3340, 2930, 1670,1600 cm⁻¹.

EXAMPLE 72 N-(2,4,6-Trimethoxy)phenyl-2-((1-n-hexyl)sulfonyl)octanamide

The title compound was prepared by treatingN-(2,4,6-trimethoxy)phenyl-2-((1-n-hexyl)thio)octanamide (0.5 g, 1.18mmol) with m-chloroperoxybenzoic acid (0.56 g, 2.76 mmol) indichloromethane (10 mL). Extractive work up and chromatography on silicagel (1:3 ethyl acetate:hexanes, eluent) providedN-(2,4,6-trimethoxy)phenyl-2-((1-n-hexyl) sulfonyl) octanamide (0.28 g,52%).

M.p. 134°-137° C. ¹ H NMR (CDCl₃) δ7.44 (s, 1); 6.17 (s, 2); 3.85 (s,3); 3.27 (m, 1); 2.20 (m, 1); 2.20-0.93 (m, 26). IR (CHCl₃) 3370, 2930,1690, 1600 cm⁻¹.

EXAMPLE 73 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-hexyl)thio)hexanamide

The title compound was prepared by a procedure similar to that describedin Examples 1 through 4.

M.p. 67°-69° C. ¹ H NMR (CDCl₃) 87.76 (bs, 1); 6.12 (s, 2); 3.78 (s, 3);3.76 (s, 3); 3.42 (t, 4 Hz, 1); 2.69-2.60 (m, 2); 1.99-1.19 (m, 14);0.92-0.79 (m, 6).

EXAMPLE 74 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-pentyl)thio)octanamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p. 85°-86° C. ¹ H NMR δ (CDCl₃) 7.78 (s, 1); 6.11 (s, 2); 3.77 (s, 3);3.74 (s, 6); 3.44 (t, 4 Hz, 1); 2.66 (m, 2); 1.90-1.22 (m, 16); 0.87 (m,6). IR (CHCl₃) 3350, 2930, 1675, 1610 cm⁻¹.

EXAMPLE 75 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-hexyl)thio)pentanamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p. 74°-75° C. ¹ H NMR (CDCl₃) δ7.81 (bs, 1); 6.15 (s, 2); 3.82 (s, 3);3.79 (s, 6); 3.48 (t, 3 Hz, 1); 2.70 (m, 2); 1.98-0.85 (m, 8). IR(CHCl₃) 3320, 2920, 1675, 1600 cm⁻¹.

EXAMPLE 76 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-hexyl)thio)heptamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p. 89°-91° C. ¹ H NMR (CDCl₃) δ7.82 (bs, 1); 6.16 (s, 2); 3.82 (s, 3);3.80 (s, 6); 3.48 (t, 3 Hz, 1); 2.70 (m, 2); 2.00-0.84 (m, 22). IR(CHCl₃) 3340, 2930, 1675, 1600 cm⁻¹.

EXAMPLE 77 AND 78N-(2,4,6-Trimethoxy)phenyl-2-((1-N-hexyl)sulfinyl)octanamide(Diastereomer A and Diastereomer B)

The title compound was prepared by treatingN-(2,4,6-trimethoxy)phenyl-2-(1-n-hexyl)thiooctamide (0.5 g, 1.2 mmol)with m-chloroperoxybenzoic acid (0. 29 g, 1.4 mmol) in dichloromethane(10 mL) at -20° C. Extractive work up and chromatography on silica gel(1:1 ethyl acetate: hexanes, eluent) provided Diastereomer A, m.p.116°-118 ° C., (less polar, 0.18 g, 33%) and Diastereomer B, m.p.105°-106° C., (more polar, 0.12 g, 12%).

EXAMPLE 79 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-hexyl)thio)butanamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p 79°-80° C. ¹ H NMR (CDCl₃) δ7.84 (bs, 1); 6.17 (s, 2); 3.82 (s, 2);3.81 (s, 6); 3.44 (t, 3 Hz, 1); 2.71 (m, 2); 2.02-0.86 (m, 16). IR(CHCl₃) 3340, 2960, 1675, 1600 cm⁻¹.

EXAMPLE 80 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-butyl)thio)octanamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p. 87°-88° C. ¹ H NMR (CDCl₃) δ7.74 (s, 1); 6.80 (s, 2); 3.75 (s, 3);(s, 6); 3.40 (t, 4 Hz, 1); 2.63 (m, 2); 2.04-1.19 (m, 14); 0.88-0.80 (m,6). IR (CHCl₃) 2930, 1680, 1605 cm⁻¹.

EXAMPLE 81 N-(2,4,6-Trimethoxy)phenyl-2-((2-thiazolyl)thio)octamide

The title compound was prepared according to the procedures described inExamples 5 and 6.

M.p. 81°-83° C. ¹ H NMR (CDCl₃) δ8.10 (s, 1); 7.62 (m, 1); 7.19 (m, 1);6.06 (s, 2); 4.40 (t, 3 Hz, 1); 3.75 (s, 3), 3.66 (s, 6); 2.2-1.22 (m,10); 0.86 (m, 3). IR (CHCl₃) 2920, 1685, 1600, 1460 cm⁻¹.

The title compounds of Examples 82-96 were prepared by a proceduresimilar to that of Examples 5 and 6.

EXAMPLE 82 N-(2,4,6-Trimethoxy)-2-((benzthiazol-2-yl)thio)octanamide

M.p. 108°-112° C. ¹ H NMR (CDCl₃) δ8.26 (s, 1); 7.78 (d, 4 Hz, 1); 7.72(d, 4 Hz, 1); 7.35 (m, 1); 6.09 (s, 1); 6.00 (s, 1); 4.98 (t, 4 Hz, 1);3.76 (s, 3); 3.70 (s, 3); 3.46 (s, 4); 2.2-1.2 (m, 10); 0.84 (m, 3). IR(CHCl₃) 2930, 1690, 1600, 1510, 1465, 1440 cm⁻¹. N Calc.: 590 Found:5.29.

EXAMPLE 83 N-(2,4,6-Trimethoxy)phenyl-2-((1-N-decyl)thio)butanamide

M.p. 58°-59° C. ¹ H NMR (CDCl₃) δ7.85 (bs, 1); 6.17 (s, 2); 3.83 (s, 3);3.80 (s, 3); 3.48 (t, 3 Hz, 1); 2.71 (m, 2); 2.06-0.86 (m, 24). IR(CHCl₃) 3350, 2910, 1675, 1600 cm⁻¹.

EXAMPLE 84 N-(N-Pentyl)-2-(2-(6-ethoxybenzthiazolyl)thio)decanamide

M.p. 48°-50° C. ¹ H NMR (CDCl₃) δ7.68 (bs, 5 Hz, 1); 7.24 (bs, 1); 7.18(d, 1 Hz, 1); 6.98 (q, 1 Hz, 1); 4.31 (t, 3 Hz, 1); 4.04 (q, 3, 6 Hz,2); 3.22 (m, 2), 2.16-0.68 (m,29). IR (CHCl₃) 3310, 2930, 1675, 1610cm⁻¹.

EXAMPLE 85 N-(2,4,6-Trifluoro)phenyl-2-(N-hexyl)thiooctanamide

M.p. 63°-66° C. ¹ H NMR (CDCl₃) δ8.08 (bs, 1); 6.70 (t, 4 Hz, 2); 3.42(t, 3 Hz, 1); 2.58 (t, 4 Hz, 2); 1.98-0.80 (m,24). IR (CHCl₃) 3666,29.23, 1692, 1644, 1511, 14.76 cm⁻¹.

EXAMPLE 86N-(2,4,6-Trimethoxy)phenyl-2-(2-(6-ethoxybenzthiazolyl)thio)octanamide

Amorphous. ¹ H NMR (CDCl₃) δ8.24 (s, 1); 7.64 (d, 6 Hz,1); 7.16 (d, 1Hz, 1); 6.92 (m, 1); 6.11 (s, 1); 6.08 (s,1); 6.00 (s, 1); 4.58 (t, 4Hz, 1); 4.00 (q, 3 Hz, 2); 3.78 (s, 3); 3.74 (s, 2) 3.70 (s, 2); 3.46(s, 3); 2.2-1.2 (m, 9); 0.85 (m, 3 Hz, 3).

EXAMPLE 87N-(2,4,6-Trimethoxy)phenyl-2-(2-(6-ethoxybenzthiazolyl)thio)pentanoamide

M.p. 44°-46° C. ¹ H NMR (CDCl₃) δ8.18 (s, 1); 7.56 (d, 5 Hz, 1); 7.07(d, 1 Hz, 1); 6.83 (m, 1); 5.91 (s, 2); 4.52 (t, 3 Hz, 1); 3.91 (q, 4Hz, 2); 3.60 (s, 3); 3.38 (s, 6); 2.10-1.10 (m, 7); 0.88 (m, 3 Hz, 3).IR (CHCl₃) 2960, 1690, 1605, 1510, 1470 cm⁻¹.

EXAMPLE 88N-(2,4,6-Trimethoxy)phenyl-2-(2-(5-chlorobenzthiolyl)thio)hexanamide

M.p. 100°-101° C. ¹ H NMR (CDCl₃) δ8.20 (s, 1); 7.65 (d, 4 Hz, 1); 7.20(m, 1); 7.08 (s, 1); 6.10 (s, 2); 4.72 (t, 4 Hz, 1); 3.79 (s, 9);2.2-1.1 (m, 10); 0.88 (m, 3 Hz, 3).

EXAMPLE 89N-(2,4,6-Trimethoxy)phenyl-2-(2-(6-ethoxybenzthiazolyl)thio)hexamide

Amorphous. ¹ H NMR (CDCl₃) δ8.28 (s, 1); 7.66 (d, 5 Hz, 1); 6.94 (m, 1);6.02 (s, 2); 4.61 (t, 4 Hz, 1); 4.03 (q, 3, Hz, 2); 3.74 (s, 3); 3.50(s, 6); 2.15 (s, 2); 1.96-1.32 (m, 7); 0.92 (t, 4 Hz, 3). IR (CHCl₃)2930, 1690, 1600, 1510, 1450 cm⁻¹.

EXAMPLE 90 N-(5-Isoquinolinyl)-2-((1-tet-nonyl)thio)hexanamide

M.p. 83°-85°. ¹ H NMR (CDCl₃) δ9.4 (s, 1); 9.2 (s, 1); 8.4 (m, 1), 7.8(m, 1); 7.6 (m, 2); 3.55 (m, 1); 2.65 (m, 2); 2.2-1.8 (m, 2); 1.0-1.80(m, 20); 0.8-1.0 (m, 6). IR (CHCl₃) 2920, 2860, 1690, 1530 cm⁻¹.

EXAMPLE 91 N-(5-Isoquinolinyl)-2-((1-N-butyl)thio)octanamide

Amorphous. ¹ H NMR (d-DMSO) δ9.42 (s, 1); 9.30 (m, 1); 8.60 (m, 1), 8.40(m, 1); 7.82 (m, 2); 7.65 (m, 2); 3.60 (m, 1); 2.65 (m, 2); 2.1 (m, 1);1.90 (m, 1); 1.2-1.8 (m, 15); 0.9 (m, 6). IR (CHCl₃) 2950, 2860, 1690,1520, 1480 cm⁻¹.

EXAMPLE 92N-(5-Isoquinolinyl)-2-(2-(6-ethoxybenzthiazolyl)thio)octanamide

M.p. 92°-93° C. ¹ H NMR (CDCl₃) δ9.13 (s, 1); 8.36 (d, 5 Hz, 1); 8.30(d, 3 Hz, 1), 7.78 (d, 6 Hz, 1); 7.70 (t, 5 Hz, 3); 7.53 (t, 4 Hz, 1);7.19 (s, 1); 7.0 (m, 1); 4.61 (t, 4 Hz, 1); 4.03 (q, 3 Hz, 2); 2.3-1.8(m, 2); 1.6-1.2 (m, 11); 0.82 (m, 3). IR (CHCl₃) 2920, 1700, 1610, 1550,1470 cm⁻¹.

EXAMPLE 93N-(2,4,6-Trifluoro)phenyl-2-(2-(6-ethoxybenzthiazolyl)thio)decanamide

Amorphous. ¹ H NMR (CDCl₃) δ8.54 (s, 1); 7.67 (d, 4 Hz, 1); 7.20 (d, 1Hz, 1); 7.00 (m, 1); 6.8-6.6 (m, 2); 4.48 (t, 3 Hz, 1); 4.03 (q, 3 Hz,2); 2.2-1.0 (m, 17); 0.84 (m, 3). IR (CHCl₃) 2920, 2840, 1700, 1600,1520 cm⁻¹.

EXAMPLE 94N-(2,4,6-Trimethoxy)phenyl-2-(2-(6-ethoxybenzthiazolyl)thio)tetradodecanamide

M.p. 87°-89° C. ¹ H NMR (CDCl₃) δ8.27 (s, 1); 7.68 (d, 5 Hz, 1); 7.20(d, 1 Hz, 1); 6.96 (m, 1); 6.04 (s, 2); 4.62 (t, 3 Hz, 1); 4.05 (q, 3Hz, 2); 3.74 (s, 3); 3.51 (s, 6); 2.2-1.2 (m, 25); 0.84 (m, 3). IR(CHCl₃) 2920, 2860, 1690, 1600, 1510 cm⁻¹.

EXAMPLE 95 N-(6-Methoxyisoquinolin-5-yl)-2-((1-n-hexyl)thio)decanamide

Amorph. ¹ H NMR (CDCl₃) δ9.1 (s, 1); 8.5 (m, 1); 8.4 (m, 1); 7.9 (m, 1);7.5 (m, 2); 7.35 (m, 2); 4.0 (s, 3); 3.5 (m, 1); 2.7 (m, 2); 2.05 (m,1); 1.85 (m, 1); 1.2-1.8 (m, 15); 0.9 (m, 6). IR (CHCl₃) 2920, 1680,1625, 1485 cm⁻¹.

EXAMPLE 96 N-(5-Isoquinolinyl-2-((1-n-butyl)thio)decanamide

M.p. 73°-75° C. ¹ H NMR (CDCl₃) δ9.8 (s, 1); 9.5 (m, 1); 8.6 (m, 1),8.35 (m, 1); 7.8 (m, 1); 7.5 (m, 2); 3.5 (m, 1); 2.65 (m, 2); 2.1-1.7(m, 18); 0.9 (m, 6). IR (CHCl₃) 2920, 1685, 1520, 1480 cm⁻¹.

EXAMPLE 97N-(2,4,6-trimethoxyphenyl)-N'-[4-(3-methylbutyl)phenylmethyl]-N'-heptylurea

209 mg (1 mmole) 2,4,6-trimethoxyphenylisocyanate, 275 mg4-(3-methylbutyl)benzylamine, and 10 ml methylene chloride were stirredat room temperature overnight. The reaction mixture was concentrated invacuo. Chromatography on 100 g silica gel eluting with 1:1 hexane-ethylacetate gave 320 mg product.

66% yield. ¹ H NMR (CDCl₃): δ0.81-0.96 (c) and 0.92 (d) (total 9H); 1.27(c, 9H); 1.44-1.68 (c, 4H); 2.6 (t, 2H); 3.33 (t, 2H); 3.75 (s, 6H);3.77 (s, 3H); 4.55 (s, 2H); 5.55 (s, 1H); 6.11 (s, 2H); 7.15 (d, 2H);7.24 (d, 2H). IR (CHCl₃): 1654 cm⁻¹.

EXAMPLE 98N-(2,4,6-trimethoxyphenyl)-N'-[4-(2,2-dimethylpropyl)phenylmethyl]-N-heptylurea

The title compound was prepared according to the procedure of Example97, but using 760 mg (3.63 mmole) 2,4,6-trimethoxyphenylisocyanate, 1.0g (3.63 mmole) 4-(2,2-dimethylpropyl)benzylamine, and 20 ml methylenechloride. There was obtained 1.25 g product.

71% yield. ¹ H NMR (CDCl₃): δ0.82-0.95 (c) and 0.89 (s) (total 12H);1.27 (c, 8H); 1.61 (c, 2H); 2.48 (s, 2H); 3.34 (t, 2H); 3.76 (s, 6H);3.78 (s, 3H); 4.57 (s, 2H); 5.59 (s, 1H); 6.12 (s, 2H); 7.1 (d, 2H);7.23 (d, 2H). IR (CHCl₃): 1657 cm⁻¹.

EXAMPLE 99 N-(6-Methylthio-8-acetaminoquinolin-5-yl)-2-(hexylthio)decanoic amide

5-Amino-6-methylthio-8-acetaminoquinoline, prepared according to theprocedure of Gilman et at. (J. Amm. Chem. Soc. 68, 1577 (1946), wascoupled with 2-hexanethiodecanoic acid (prepared as described in Example25) using the procedure described in Example 25, to give the titlecompound.

¹ H NMR (CDCl₃) δ9.75 (s, 1H); 8.82 (s, 1H); 8.68 (d, 5Hz, 1H); 8.46 (s,1H); 7.97 (d, 7 Hz, 1H); 7.41 (dd, 5 & 7Hz, 1H); 3.50 (t, 6 Hz, 1H);2.79 (t, 6 Hz, 2H); 2.58 (s, 3H); 2.35 (s, 3H); 2.13 (m, 1H); 1.85 (m,1H); 1.76-1.22 (m, 20H); 0.86 (m, 6H).

¹³ C NMR (CDCl₃) δ172.1, 169.0, 147.1, 136.4, 136.1, 134.5, 131.6,125.2, 122.3, 113.1, 59.8, 51.1, 33.1, 32.3, 31.9, 31.4, 29.4, 29.3,28.6, 27.8, 25.1, 22.6, 22.5, 15.3, 14.1.

IR (KBr): 3240, 2920, 1640, 1650, 1530 cm⁻¹.

The title compounds of Examples 100-107 were prepared according to theprocedure described in Example 4.

EXAMPLE 100 2-(4-t-Butylphenylthio)-N-(2,4,6-trimethoxyphenyl)octanamide

IR (CHCl₃): 1670 cm¹.

EXAMPLE 101 2-(4-t-Butylphenylthio)-N-(2,4,6-triethylphenyl)octanamide

IR (CHCl₃): 1670 cm⁻¹.

EXAMPLE 1022-[4-(1,1-Dimethylpropyl)phenylthio]-N-(2,4,6-trimethylphenyl)nonanamide

IR (CHCl₃): 1670 cm⁻¹.

EXAMPLE 103 2-(4-n-Butylphenylthio)-N-(2,4,6-trimethylphenyl)nonanamide

IR (CHCl₃): 1669 cm⁻¹.

EXAMPLE 1042-[4-(1,1-Dimethylpropyl)phenoxy]-N-(2,4,6-trimethoxyphenyl)octanamide

IR (CHCl₃): 1681 cm⁻¹.

EXAMPLE 1052-[4-(1,1-Dimethylpropyl)phenoxy]-N-(2,4,6-trimethylphenyl)octanamide

IR (CHCl₃): 1678 cm¹.

EXAMPLE 106 2-(4-n-Propylphenol)-N-(2,4,6-trimethylphenyl)decanamide

IR (CHCl₃): 1678 cm⁻¹.

EXAMPLE 107 2-(4-n-Propylphenylthio)-N-(2,4,6-trimethylphenyl)nonanamide

IR (CHCl₃): 1669 cm⁻¹.

The title compounds of Examples 108-120 were prepared according to theprocedure described in Examples 5 and 6.

EXAMPLE 108

N-(2,4,6-Trimethyl)phenyl-2-((2-methylfuryl)thio)octanamide

M.p. 73°-75° C.

EXAMPLE 109N-(2,4,6-Trimethyl)phenyl-2-((2-benzimidazolyl)thiodecanamide

M.p. 171°-172° C.

EXAMPLE 110N-(2,4,6-Trimethyl)phenyl-2-((2-benzothiazolyl)thio)octanamide

M.p. 103°-106° C.

EXAMPLE 111 N-(2,4,6-Trimethyl)phenyl-2-(1-hexylthio)octanamide

M.p. 69°-72° C.

EXAMPLE 112N-(2,4,6-Trimethyl)phenyl-2-[2-(3-hydroxyl-2-pyridyl)thio]decanoamide

IR (CHCl₃): 3200, 2920, 1675 cm⁻¹.

EXAMPLE 113N-(2,4,6-Trimethyl)phenyl-2-[2-(6-chlorobenzothiazolyl)thio]octamide

M.p. 130°-131° C.

EXAMPLE 114 N-(2,4,6-Trimethyl)phenyl-2-(1-heptylthio)octanamide

M.p. 53°-56° C.

EXAMPLE 115 N-(Isoquinolin-5-yl)-2-(1-heptylthio)decanamide

M.p. 71° C.

EXAMPLE 116 N-(2,4,6-Trimethyl)phenyl-2-(tert-butylthio)octanamide

M.p. 145°-147° C.

EXAMPLE 117 N-(Isoquinolin-5-yl)-2-(4-propylphenylthio)decanoic amide

M.p. 86°-88° C.

EXAMPLE 118 N-(Isoquinolin-5-yl)-2-(phenylmethylthio)decanoic amide

M.P. 86°-88° C.

EXAMPLE 119 N-(Isoquinolin-5-yl)-2-(cyclohexylthio)decanoic amide

M.p. 98°-100° C.

EXAMPLE 120 N-(Quinolin-5-yl)-2-(hexylthio)decanoic amide

IR (KBr) cm⁻¹ : 3240, 2920, 2850, 1657, 1529.

The title compounds of Examples 121-122 were prepared according to theprocedure described in Example 31.

EXAMPLE 121 N-(6-Methylquinolin-5-yl)-2-(hexylthio)decanoic amide

Mass spectrum m/e (relative intensity): M+ 428.26 (1), 312.22 (23),213.06 (30), 200.10 (23), 158.06 (100). High resolution mass spectra:m/e 428.2843, calc'd for C₂₆ H₄₀ N₂ OS: 428.2853. Anal.: Calc'd for C₂₆H₄₀ N₂ OS: C, 72.85; H, 9.41; N, 6.54. Found: C, 73.04; H, 9.20; N,6.52.

EXAMPLE 122N-(4-Methoxcarbonyl-6-methoxyquinolin-5-yl)-2-(hexylthio)decanoic amide

IR (CHCl₃) cm⁻¹ : 3320, 2915, 2862, 1748, 1651.

EXAMPLE 123 N-(Quinolin-5-yl)-2-(decyl)cyclopentane carboxamide

5-Aminoquinoline was converted to the title compound according to theprocedure described in Example 30.

M.p. 75° C.

EXAMPLE 124 N-(6-Methoxyquinolin-5-yl)-2-(decyl)cyclopentanecarboxamide

6-Methoxy-5-aminoquinoline, prepared according to the procedure ofExample 33, was converted to the title compound according to theprocedure described in Example 30.

M.p. 57°-58° C.

EXAMPLE 125 N-(6-Methoxyquinolin-5-yl)-2-(4-sec-butylphenoxy)nonanoic

The title compound was prepared according to the procedure described inExample 4.

Anal: calc'd for C₂₉ H₃₈ N₂ O₃ : C, 75.35; H, 8.28; N, 6.06. Found: C,74.81; H, 8.24; N, 5.96.

EXAMPLE 126N-(6-Methoxyquinolin-5-yl)-2-octanyl-1,3-dithiane-2-carboxamide

5-Amino-6-methoxyquinoline, prepared as described in Example 60, wascoupled with 2-octanyl-1,3-dithiane-2-carboxylic acid, prepared bytreatment of 1,3-dithiane-2-carboxylic acid with sodiumhexamethyldisilazide and octanyl bromide, according to the proceduredescribed in Example 48 to give the title compound.

Oil. ¹ H NMR(CDCl₃): δ9.00 (s, 1H); 8.63 (d, 4 Hz, 1H); 7.94 (d, 10 Hz,1H); 7.92 (d, 9 Hz, 1H); 7.73 (d, 10 Hz, 1H); 7.13 (dd, 4 & 12 Hz, 1H);3.94 (s, 3H); 3.10 (dr, 2 & 12 Hz, 2H); 2.70 (dt, 4 & 12 Hz, 2H); 2.07(m, 2H); 1.96 (m, 2H); 1.60 (m, 2H); 1.31-1.08 (m, 10H); 0.87 (t, 6 Hz,3H).

The title compounds of Examples 127-131 were prepared according to theprocedure described in Example 35.

EXAMPLE 127 N-(6-Cyclohexylthio)quinolin-5-yl)-2-hexylthiodecanoicamide

M.p. 88°-89° C.

EXAMPLE 128 N-(6-(3-Phenylpropylthio)quinolin-5-yl)-2-hexylthiodecanoicamide

M.p. 63°-64° C.

EXAMPLE 129 N-(6-(benzylthio)quinolin-5-yl)-2-hexylthiodecanoic amide

Anal: calc'd for C₃₂ H₄₄ N₂ OS₂ : C, 71.48; H, 8.50; N, 5.20. Found: C,71.59; H, 8.26; N, 5.21.

EXAMPLE 130 N-(6-(hexylthio) quinolin-5-yl)-2-hexylthiodecanoic amide

Anal: calc'd for C₃₁ H₅₀ N₂ OS₂ : C, 70.13; H, 9.49; N, 5.28. Found: C,69.99; H, 9.37; N, 5.42.

EXAMPLE 131 N-(6-chloroquinoline-5-yl]-2-hexylthiodecanoic amide

Anal: calc'd for C₂₅ H₃₇ ClN₂ OS: C, 66.06; H, 8.7; N, 5.42. Found: C,66.86; H, 8.31; N, 6.24.

The title compounds of Examples 132-141 were prepared according to theprocedure described in Examples 54-59.

EXAMPLE 132Exo-3-n-nonyl-endo-N-(2,4,6-trimethylphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR (CHCl₃): 1659 cm⁻¹.

EXAMPLE 133Exo-3-n-heptyl-endo-N-(2,4,6-trimethylphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR (CHCl₃): 1660 cm⁻¹.

EXAMPLE 134Exo-3-n-octyl-endo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR (CHCl₃): 1660 cm⁻¹.

EXAMPLE 135Endo-3-n-octyl-exo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR (CHCl₃): 1677 cm⁻¹.

EXAMPLE 136Endo-3-n-heptyl-exo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR (CHCl₃): 1670 cm⁻¹.

EXAMPLE 137Exo-3-n-heptyl-endo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR (CHCl₃) 1660 cm⁻¹.

EXAMPLE 138Exo-3-n-heptyl-endo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.2]oct-5-ene-2-carboxamide

IR (CHCl₃): 1664 cm⁻¹.

EXAMPLE 139Endo-3-n-heptyl-exo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.2]oct-5-ene-2-carboxamide

IR (CHCl₃): 1680 cm⁻¹.

EXAMPLE 140 Exo-3-n-nonyl-endo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.2]oct-5-ene-2-carboxamide

IR (CHCl₃): 1666 cm⁻¹.

EXAMPLE 141 Endo-3-n-nonyl-exo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.2]oct-5-ene-2-carboxamide

IR (CHCl₃): 1679 cm⁻¹.

EXAMPLE 142 2-n-Nonyl-N-(2,4,6-trimethylphenyl)indane-2-carboxamide

The title compound was prepared according to the procedure described inExamples 60-64.

IR (CHCl₃): 1671 cm⁻¹.

The title compounds of Examples 143-144 were prepared according to theprocedure described in Examples 55-59.

EXAMPLE 143Exo-2-n-decyl-endo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR (CHCl₃) 1676 cm⁻¹.

EXAMPLE 144Endo-2-n-decyl-exo-N-(2,4,6-trimethoxyphenyl)-bicyclo-[2.2.1]hept-5-ene-2-carboxamide

IR 1675 cm⁻¹.

The title compounds of Examples 145-147 were prepared according to theprocedure described in Examples 60-64.

EXAMPLE 1452-n-Octyl-N-(2,4,6-trimethylphenyl)-1,2,3,4-tetrahydro-2-naphthamide

¹ H NMR: δ0.87 (t, 3H); 1.29 (c, 10H); 1.52 (c, 3H); 1.89 (c) and 1.191(s) (total 8H); 2.2 (s, 3H); 2.3 (c, 1H); 2.91 (c) and 2.94 (d) (total3H); 3.19 (d, 2H); 6.76 (s, 1H); 6.79 (s, 2H); 7.12 (s, 4H).

EXAMPLE 146 2-n-Decyl-N-(2,4,6-trimethylphenyl)indane-2-carboxamide

IR (CHCl₃) 1671 cm⁻¹.

EXAMPLE 1472-n-Nonyl-N-(2,4,6-trimethylphenyl)-1,2,3,4-tetrahydro-2-naphthamide

IR (CHCl₃) 1668 cm⁻¹.

The title compounds of Examples 148-150 were prepared according to theprocedure described in Examples 5 and 6.

EXAMPLE 148 N-(2,6-Difluoro)phenyl-2-((1-N-hexyl)thio)octanamide

M.p. 46°-48° C.

EXAMPLE 149 N-(2,6-Difluoro)phenyl2-(2-(6-ethoxybenzthiazolyl)thio)octanamide

M.p. 110°-112° C.

EXAMPLE 150N-(2,6-Difluoro)phenyl-2-(2-(6-ethoxybenzthiazolyl)thio)decanamide

M.p. 99°-100° C.

EXAMPLE 151 N-(6-acetaminoquinolin-5-yl)-2-(hexylthio)decanoic amide

Commercially available 5-amino-6-nitroquinoline was reduced to5,6-diaminoquinoline using a procedure analogous to that described inExample 34, except tin (II) chloride was used in place of iron.5,6-Diaminoquinoline was converted to 5-amino-6-acetaminoquinoline byreaction with acetic anhydride and pyridine. Using the procedureoutlined in Example 25, 5-amino-6-acetaminoquinoline and2-(hexylthio)decanoic acid were coupled to give the title compound. Massspectrum m/e: 471.3 (M+).

¹ H NMR, δ(CDCl₃): 8.99 (s, 1H); 8.85 (dd, J=2 & 4 Hz, 1H); 8.37 (s,1H); 8.14 (d, J=10 Hz, 1H), 7.89 (d, J=9 Hz, 1H); 7.79 (d, J=9 Hz, 1H);7.36 (dd, J=4 & 10 Hz, 1H); 3.47 (t, J=8 Hz, 1H); 2.64 (t, J=8 Hz, 2 H);2.13 (s, 3H): 1.87 (m, 2H); 1.28 (br m, 20 H); 0.87 (m, 6H).

EXAMPLE 152 N-(6-aminoquinolin-5-yl)-2-(hexylthio)decanoic amide

N-(6-Acetaminoquinolin-5-yl)-2-(hexylthio)decanoic amide, prepared asdescribed in Example 151, was treated with aqueous hydrochloric acid andisopropanol to give the title compound. Mass spectrum m/e: 428.3 (M+-1).

¹ H NMR, δ(CDCl₃): 8.94 (d, J=6 Hz); 8.93 (d, J=2 Hz, 1H), 7.93 (d, J=9Hz, 1H); 7.73 (d, J=9 Hz, 1H); 7.50 (dd, J=2 & 6 Hz, 1H); 4.33 (t, J=7Hz, 1H); 2.43 (m, 2H), 2.00 (m, 2H); 1.48 (m, 4 H); 1.19 (m, 16H); 0.81(m, 6 H).

EXAMPLE 153 N-(6-methylthioquinolin-5-yl)oleamide

5-Amino-6-methylthioquinoline, prepared as described in Example 34, andcommercially available oleoyl chloride were coupled to give the titlecompound according to the procedure described in Example 25. Massspectrum m/e: 454.3 (M+).

¹ H NMR, δ (CDCl₃): 8.77 (d, J=3 Hz, 1 H); 8.00 (d, J=6 Hz, 1H); 7.98(d, J=7 Hz, 1H) 7.59 (d, J=6 Hz, 1H); 7.32 (dd, J=3 & 7 Hz, 1H); 7.14(s, 1H); 5.32 (br s, 2H); 2.51 (s, 5H) 1.99 (br s, 4H); 1.81 (m, 2H);1.30 (br s, 20H); 0.84 (t, J=6 Hz, 3H).

EXAMPLE 154 N-(8-amino-6-methoxyquinolin-5-yl)-2-hexylthiodecanoicamide

Commercially available 6-methoxy-8-aminoquinoline (Chemical ProcurementLaboratories) was acetylated with acetic anhydride and pyridine. Theresultant 6-methoxy-8-acetaminoquinoline was nitrated and reduced usingthe procedure described in Example 33 to give5-amino-6-methoxy-8-acetaminoquinoline. This product was coupled with2-(hexylthio)decanoic acid according to Example 25 and hydrolyzed withaqueous hydrochloric acid and isopropanol to give the title compound.Mass spectrum m/e: 459.3 (M+).

¹ H NMR, δ(CDCl₃): 8.52 (d, J=4 Hz, 1H), 8.19 (s, 1H); 7.85 (d, J=8 Hz,1H); 7.27 (dd, J=4 & 8 Hz, 1H); 6.60(s, 1H); 5.06 (br s, 2H); 3.82 (s,3H); 3.48 (t, J=6 Hz, 1H); 2.27 (t, J=7 Hz, 2H), 2.01 (m, 1H); 1.82 (m,1H); 1.63 (m, 2H); 1.28 (m, 18H); 0.86 (m, 6H).

EXAMPLE 155N-(6-(1,2,4-triazol-3-yl)thioquinolin-5-yl)-2-hexylthiodecanoic amide

Using a procedure analogous to that described in Example 34,5-amino-6-(1,2,4-triazol-3-yl)quinoline was synthesized and coupled with2-(hexylthio)decanoic acid to give the title compound.

Analysis: C 62.94, H 7.56, N 13.34; calc. for C₂₇ H₃₉ N₅ OS₂ : C 63.12,H 7.65, N 13.63.

¹ H NMR, δ (CDCl₃): 9.59 (s, 1H), 8.89 (d, J=5 Hz, 1H); 8.18 (d, J=9 Hz,1 H); 8.06 (s, 1H); 7.93 (d, J=9 Hz, 1H); 7.65 (d, J=9 Hz, 1H), 7.43(dd, J=5 & 9 Hz, 1H), 3.50 (t, J=7 Hz, 1H); 2.74 (t, J=7 Hz, 2H), 2.04(m, 1H); 1.70 (m, 1H); 1.59 (m, 3H); 1.25 (m, 18H); 0.86 (m, 6H).

EXAMPLE 156 N-(6-methylthioquinolin-5-yl)-2,2-di(hexylthio)acetamide

2,2-Di (hexylthio) acetic acid was synthesized from dichloroacetic acidand hexanethiol using a procedure similar to that described inExample 1. 2, 2-Di(hexylthio)acetic acid and5-amino-6-methylthioquinoline were coupled to give the title compoundusing the procedure described in Example 25.

Mass spectrum m/e: 464.2 (M+).

¹ H NMR δ(CDCl₃): 8.83 (dd, J=3 & 4 Hz, 1H); 8.45 (s, 1H), 8.12 (d, J=8Hz, 1H); 8.09 (d, J=8 Hz, 1H); 7.64, d, J=8 Hz, 1 H); 7.42 (dd, J=4 & 8,1H); 4.51 (s, 1H); 2.89 (t, J=8 Hz, 4H); 2.57 (s, 3H), 1.68 (m, 6H),1.44 (m, 6H); 1.32 (m, 8H); 0.81 (t, J=7 Hz, 6H).

EXAMPLE 157 N-(6-methylthioquinolin-5-yl)-2-heptylnonanoic amide

By use of the procedures described in Example 25, nonanoic acid wasalkylated with heptyl bromide and the resulting product was coupled with5-amino-6-methylthioquinoline (Example 34) to give the title compound.

Mass spectrum m/e: 428.3 (M+-SCH₃).

¹ H NMR (CDCl₃): δ8.77 (d, J=4 Hz, 1H); 8.00 (d, J=8 Hz, 1H); 7.95 (d,J=8 Hz, 1H); 7.55 (d, J=8 Hz, 1H); 7.49 (s, 1H); 7.31 (dd, J=4 & 8 Hz,1H); 2.49 (s, 3H); 2.43 (m, 1H); 1.40 (br, 24H); 0.85 (t, J=6 Hz, 6H).

EXAMPLE 158N-(6-methylthioquinolin-5-yl)-2-[2-(6-ethoxybenzthiazolyl)-thio]decanoicamide

The title compound was prepared by procedures analogous to those asdescribed in Examples 5 and 6.

MP: 139°-141° C.

¹ H NMR (CDCl₃): δ9.42 (s, 1H); 8.76 (d, 3 Hz, 1H); 8.00 (d, 9 Hz, 2H);7.74 (d, 9 Hz, 1H); 7.60 (d, 9 Hz, 1H); 7.21 (m, 2H); 6.98 (dd, 3 & 9Hz, 1H); 4.71 (t, 7 Hz, 1H); 4.05 (q, 7 Hz, 2H); 2.53 (s, 3H); 2.30 (m,1H); 1.97 (m, 1H); 1.59 (m, 2H); 1.45-1.25 (m, 10H); 1.00-0.81 (m, 6H).

FABMS m/e: 554 (M⁺ +1)

Anal.: Calc'd for C₂₉ H₃₅ N₃ O₂ S₃ 1/2 H₂ O: C, 61.89; H, 6.45; N, 7.46.Found: C, 62.14; H, 6.33; N, 7.43.

EXAMPLE 159N-(3-methyl-6-chloro-8-acetaminoauinolin-5-yl)-2-(hexylthio)decanoicamide

3-Methyl-5-amino-6-chloro-8-acetaminoquinoline, prepared according tothe procedures of Utermohlen, W. P., J. Org. Chem., 8, 544 (1943) andGilman et al. , J. Am. Chem. Soc., 68, 1577 (1946), was coupled with2-hexanethiodecanoic acid (prepared as described in Example 25) usingthe procedure described in Example 25, to give the title compound.

MP: 140°-141° C.

¹ H NMR (CDCl₃): δ9.68 (s, 1H); 8.72 (s, 1H); 8.57 (s, 2H); 7.76 (s,1H); 3.52 (t, 7 Hz, 1H); 2.75 (t, 7 Hz, 2H); 2.49 (s, 3H); 2.33 (s, 3H);2.13-1.28 (m, 22H); 0.87 (m, 6H).

EIMS m/e: 519 (M⁺)

Anal.: Calc'd for C₂₈ H₄₂ N₃ O₂ SCl; C, 64.66, H, 8.14; N, 8.07. Found:C, 64.65; H, 8.39; N, 7.96.

EXAMPLE 160N-(3-methyl-6-methylthio-8-acetaminoquinolin-5-yl)-2-(hexylthio)decanoicamide

3-Methyl-5-amino-6-methylthio-8-acetaminoquinoline, prepared accordingto the procedures of Utermohlen, W. P., J. Org. Chem., 8, 544 (1943) andGilman et al. J. Am. Chem. Soc., 68, 1577 (1946), was coupled with2-hexanethiodecanoic acid (prepared as described in Example 25) usingthe procedure described in Example 25, to give the title compound.

MP: 128°-131° C.

¹ H NMR (CDCl₃): δ9.75 (s, 1H); 8.76 (s, 1H); 8.54 (s, 1H); 8.38 (s,1H); 7.74 (s, 1H); 3.52 (t, 7 Hz, 1H); 2.80 (t, 7Hz, 2H); 2.58 (s, 3H);2.48 (s, 3H); 2.34 (s, 3H); 2.15-1.22 (m, 22H); 0.87 (m, 6H).

EIMS m/e: 531 (M⁺)

Anal.: Calc'd for C₂₉ H₄₅ N₃ O₂ S₂ : C, 65.50; H, 8.53; N, 7.90. Found:C, 65.33; H, 8.55; N, 7.85.

EXAMPLE 161 N-(3-methyl-6-methylthioquinolin-5-yl)-2-(hexylthio)decanoicamide

3-Methyl-5-amino-6-methylthioquinoline, prepared according to theprocedures of Utermohlen, W. P., J. Org. Chem., 8, 544 (1943) and Gilmanet al., J. Am. Chem. Soc., 68, 1577 (1946), was coupled with2-hexanethiodecanoic acid (prepared as described in Example 25) usingthe procedure described in Example 25, to give the title compound.

M.p.: 137°-138° C.

¹ H NMR (CDCl₃): δ 8.69 (d, 2 Hz, 1H) ; 8.52 (s, 1H); 8.02 (d, 9 Hz, 1H); 7.79 (s, 1H); 7.58 (d, 9 Hz, 1H); 3.54 (t, 7 Hz, 1H); 2.81 (t, 7 Hz,2H); 2.55 (s, 3H); 2.49 (s, 3H); 2.15-1.25 (m, 22H); 0.87 (m, 6H).

EIMS m/e: 474 (M⁺)

Anal.: Calc'd for C₂₇ H₄₂ N₂ OS₂ ; C, 68.31; H, 8.91; N, 5.90. Found: C,68.52; H, 8.94; N, 5.91.

EXAMPLE 162 N-(6-nitroquinoline-5-yl)-2-(hexylthio)decanoic amide

Commercially available 5-amino-6-nitroquinoline was coupled with2-hexanethiodecanoic acid (prepared as described in Example 25) usingthe procedure described in Example 25, to give the title compound.

M.p.: 89.91° C.

¹ H NMR (CDCl₃): δ 10.10 (s, 1H); 9.05 (dd, 2 & 4 Hz, 1H); 8.26 (d, 9Hz, 1H); 8.24 (m, 1H); 8.09 (d, 9 Hz, 1H); 7.52 (dd, 4 & 9 Hz, 1H); 3.48(dd, 6 & 8 Hz, 1H); 2.65 (m, 2H); 2.05 (m, 1H); 1.86 (m, 1H); 1.70-1.20(m, 20H); 0.87 (t, 6 Hz, 6H).

FABMS m/e: 460 (M⁺ +H)

Anal.: Calc'd for C₂₅ H₃₇ N₃ O₃ S: C, 65.33; H, 8.11; N, 9.14. Found: C,65.42; H, 8.13; N, 9.23.

EXAMPLE 163 N-(6-N,N-dimethylaminoquinolin-5-yl)-2-(hexylthiol)decanoicamide

5-Nitro-6-chloroquinoline, prepared as described by Maneke & Kulka,Organic Reactions, Vol. VII, 59 (1953) and Campbell et al., J. Am. Chem,Soc., 68, 1559 (1946), was allowed to react with dimethylamine to yield5-nitro-6-dimethylaminoquinoline. This material was converted to thetitle compound by the procedure described in Example 33.

M.p.: Oil

¹ H NMR (CDCl₃): δ8.80 (dd, 2 & 4 Hz, 1H); 8.69 (s, 1H); 8.02 (m, 1H);8.00 (d, 9 Hz, 1H); 7.60 (d, 9 Hz, 1H); 7.35 (dd, 4 & 9 Hz, 1H); 3.50(t, 8 Hz, 1H); 2.77 (s, 6H); 2.73 (t, 7 Hz, 2H); 2.12 (m, 1H); 1.86 (m,1H); 1.72-1.25 (m, 20H); 0.87 (m, 6H).

FABMS m/e: 458 (M⁺ +H)

Anal.: Calc'd for C₂₇ H₄₃ NSO: C, 70.85; H, 9.47; N, 9.18; Found: C,70.59; H, 9.31; N, 9.10.

EXAMPLE 164 N-(6-trifluoromethylquinolin-5-yl)-2-(hexylthio)decanoicamide

5-Nitro- 6-trifluoromethylquinoline, prepared as described by Manske &Kulka, Organic Reactions, Vol. VII, 59 (1953) and Campbell et al., J.Am. Chem. Soc., 68, 1559 (1946), was converted to the title compound bythe procedure described in Example 33.

M.p.: oil

¹ H NMR (CDCl₃): δ10.98 (s, 1H); 9.01 (d, 2 Hz, 1H); 8.96 (dd, 2 & 4 Hz,1H); 8.26 (dd, 2 & 8 Hz, 1H); 7.83 (s, 1H); 7.57 (dd, 4 & 8 Hz, 1H);3.52 (t, 7 Hz, 1H); 2.61 (m, 2H); 2.02 (m, 1H); 1.84 (m, 1H); 1.65-1.15(m, 20 H); 0.84 (t, 7 Hz, 3H); 0.78 (t, 7 Hz, 3H).

FABMS m/e: 483 (M⁺ +H)

Anal.: Calc'd for C₂₆ H₃₇ N₂ SOF₃ : C, 64.70; H, 7.73; N, 5.80; Found:C, 64.37; H, 7.81; N, 5.71.

EXAMPLE 165 N-(cinnolin-5-yl)-2-(hexylthio)decanoic amide

The title compound was prepared by a procedure analogous to thatdescribed in Example 33.

M.p.: 54°-56° C.

¹ H NMR (CDCl₃): δ9.41 (s, 1H); 9.36 (d, 6 Hz, 1H); 8.40 (d, 9 Hz, 1H) ;8.33 (d, 7 Hz, 1H); 7.86 (m, 2H); 3.54 (t, 6 Hz, 1H); 2.63 (t, 7 Hz,2H); 2.03 (m, 1H); 1.81 (m, 1H); 1.68-1.20 (m, 20H); 0.84 (m, 6H).

HRFABMS m/e: 416.2805 (C₂₄ H₃₇ N₃ SO+H⁺ requires 416.2738)

EXAMPLE 166 N-(cinnolin-8-yl)-2-(hexylthiol)decanoic amide

The title compound was prepared by a procedure analogous to thatdescribed in Example 33.

M.p.: oil

¹ H NMR (CDCl₃): δ11.10 (s, 1 H); 9.34 (d, 6 Hz, 1H); 8.88 (dd, 1 & 8Hz, 1H); 7.86 (d, 6 Hz, 1H); 7.76 (t, 8 Hz, 1H); 7.50 (dd, 1 & 8 Hz,1H); 3.53 (t, 7 Hz, 1H); 2.62 (t, 7 Hz, 2H); 2.03 (m, 1H); I. 86 (m,1H); 1.65-1.15 (m, 20H); 0.81 (m, 6H).

HREIMS m/e: 415.2648 (C₂₆ H₃₇ N₃ SO requires 415.2660)

EXAMPLE 167 N-(6-methylthiophthalazin-5-yl) oleic amide

5-Nitro-6-methylthiophthalazine, prepared as described by Sturrock etal., Can. J. Chem., 49, 3047 (1971) and Hirsch & Orphanos, J.Heterocyclic Chem., 2, 206 (1965), was reduced with tin (II ) chlorideand HCl to yield 5-amino-6-methylthiophthalazine. This material wascoupled with commercially available oleoyl chloride to yield the titlecompound.

M.p.: oil

¹ H NMR (CDCl₃): δ9.34 (s,2H); 7.74 (d, 8 Hz, 1H); 7.73 (s, 1H); 7.66(d, 8 Hz, 1H); 5.34 (t, 5 Hz, 2H); 2.57 (t, 8 Hz, 2H); 2.54 (s, 3H);2.01 (m, 4H); 1.81 (m, 2H); 1.50-1.10 (m, 20H); 0.86 (t, 6 Hz, 3H).

FABMS m/e: 456 (M⁺ +1)

EXAMPLE 168 N-[2,4-bis(methylthio)pyridin-3-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 13.2% yield according to theprocedure of Example 4A.

¹ H NMR (CDCl₃): δ0.86 (c, 6H); 1.17-1.76 (c, 21H), 2.03 (m, 1H), 2.42(s, 3H); 2.51(s, 3H); 2.77 (t, 2H); 3.46 (t, 1H); 6.82 (d, 1H), 8.23 (s,1H); 8.26 (d, 1H).

IR (CHCl₃): 2920, 2851, 1679, 1553, 1465 cm⁻¹.

EXAMPLE 169 N-[4,6-bis(methylthio)pyrimidin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 7% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.87 (c, 6H); 1.2-1.85 (c, 21 H); 2.02 (m, 1H); 2.52(s, 6H); 2.74 (t, 2H); 3.45 (t, 1H); 8.18 (s, 1H); 8.65 (s, 1H).

IR (CHCl₃): 2923, 2852, 1681, 1521, 1466, 1406, 1357 cm⁻¹.

EXAMPLE 170 N-(6-methoxyisoquinolin-5-yl)-2-hexylthiodecanoic amide

The title compound was prepared in 62% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.89 (c, 6H); 1.20-1.96 (c, 21 H); 2.07 (m, 1H); 2.75(t, 2H); 3.55 (t, 1H); 4.0 (s, 3H); 7.39 (d, 1H); 7.48 (d, 1H); 7.94 (d,1H); 8.45 (d, 1H); 8.52 (s, 1H); 9.14 (s, 1H).

IR (CHCl₃): 2922, 2852, 1674, 1624, 1465, 1380, 1323, 1267 cm⁻¹.

EXAMPLE 171 N-(6-methoxyquinazolin-5-yl)-2-hexylthiodecanoic amide

The title compound was prepared in 15% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.88 (c, 6H); 1.18-1.94 (c, 21H); 2.08 (m, 1H); 2.71(t, 2H); 3.55 (t, 1H); 4.0 (s, 3H); 7.69 (d, 1H); 8.0 (d, 1H); 8.78 (s,1H); 9.21 (s, 1H); 9.31 (s, 1H).

IR (CHCl₃): 2923, 2852, 1682, 1621, 1573, 1496, 1476, 1465, 1372, 1319,1273, 1255, 1222 cm⁻¹.

EXAMPLE 172 N-(4,6-dimethoxypyrimidin-5-yl)-2-hexylthiodecanoic amide

The title compound was prepared in 40% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.88 (c, 6H); 1.22-2.0 (c, 22H); 2.64 (m, 1H); 3.43(t, 1H); 3.97 (s, 6H); 7.90 (s, 1H); 8.33 (s, 1H).

IR (CHCl₃): 2922, 2852, 1680, 1582, 1491, 1465, 1410, 1399, 1312 cm⁻¹.

EXAMPLE 173 N-(4,6-diethoxypyrimidin-5-yl)-2-hexylthiodecanoic amide

The title compound was prepared in 76% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (c, 6H); 1.19-1.70 (c, 27H); 1.82 (m, 1H); 2.64(m, 2H); 3.45 (t, 1H); 4.39 (q, 4H); 7.89 (s, 1H); 8.28 (s, 1H).

IR (CHCl₃): 2924, 2853, 1681, 1582, 1491, 1441, 1386, 1315 cm⁻¹.

EXAMPLE 174 N-[4-methoxy-6-(4-methoxyphenylthio)pyrimidin-5-yl]-2-hexylthiodecanoic amide

The title compound was prepared in 6% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (m, 6H), 1.17-2.04 (c, 22H); 2.72 (t, 2H); 3.50(t, 1H); 3.83 (s, 3H); 3.96 (s, 3H); 6.94 (d, 2H); 7.44 (d, 2H); 8.17(s, 1H); 8.37 (s, 1H).

IR (CHCl₃): 2900, 2840, 1700, 1600, 1565, 1480.

EXAMPLE 175 N-(4,6-bis(ethylthio)pyrimidin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 8% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.17-2.06 (c, 28H); 2.62 (m, 4H); 2.75(t, 2H); 3.45 (t, 1H); 8.15 (s, 1H); 8.61 (s, 1H).

IR (CHCl₃): 2922, 2852, 1706, 1520, 1466, 1405, 1355 cm⁻¹.

EXAMPLE 176N-[4-methoxy-6-(2-ethoxyethylthio)pyrimidin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 38% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.16-1.85 (c) and 1.19 (t) (total 24H);1.94 (m, 1H); 2.68 (t, 2H); 3.32-3.57 (c), 3.52 (q) (total 5H); 3.65 (t,2H), 3.95 (s, 3H); 8.03 (s, 1H); 8.47 (s, 1H).

IR (CHCl₃): 2952, 2925, 2854, 1684, 1562, 1541, 1481, 1408, 1385 cm⁻¹.

EXAMPLE 177N-[2-(4-pyridinylthio)-4-methylpyridin-3-yl]-2-hexylthiodecanoic amide

The title compound was prepared in 10% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.86 (m, 6H); 1.17-1.84 (c, 21H); 1.95 (m, 1H); 2.30(s, 3H); 2.62 (t, 2H); 3.4 (t, 1H); 7.17 (d, 1H); 7.27 (m, 2H); 8.31 (d,1H); 8.48 (b, 2H); 8.55 (s, 1H).

IR (CHCl₃): 2921, 2851, 1680, 1574, 1471 cm⁻¹.

EXAMPLE 178N-[4-methoxy-6-(1-methyl-5-tetrazolythio)pyrimidin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 43% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.18-1.87 (c, 21H); 1.98 (m, 1H); 2.65(t, 2H); 3.49 (t, 1H); 4.02 (s, 3H); 4.12 (s, 3H); 8.26 (s, 1H); 8.58(s, 1H).

IR (CHCl₃): 2900, 2840, 1690, 1560, 1485 cm⁻¹.

EXAMPLE 179N-[2-(2-furylmethylthio)-4-methylpyridin-3-yl]-2-hexylthiodecanoic amide

The title compound was prepared in 10% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.17-2.03 (c, 22H); 2.19 (s, 3H), 2.65(m, 2H); 3.42 (t, 1H); 4.47 (s, 2H); 6.24 (m, 2H); 6.92 (d, 1H); 7.30(d, 1H); 8.18 (s, 1H); 8.25 (d, 1H).

IR (CHCl₃): 2920, 2850, 1706, 1675, 1481 cm⁻¹.

EXAMPLE 180 N-[2,4,6-tris(methylthio)pyrimidin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 79% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (c, 6H); 1.17-1.86 (c, 21H); 2.01 (m, 1H); 2.50(s, 6H); 2.56 (s, 3H); 2.73 (t, 2H); 3.43 (t, 1H); 8.06 (s, 1H).

IR (CHCl₃): 2922, 2852, 1686, 1499, 1465, 1347 cm⁻¹.

EXAMPLE 181 N-(2,4,6-trimethoxypyrimidin-5-yl)-2-hexylthiodecanoicamide

The title compound was prepared in 74% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): 0.87 (m, 6H); 1.18-2.0 (C, 22H); 2.63 (m, 2H); 3.42 (t,1H); 3.93 (s, 6H); 3.95 (s, 3H); 7.71 (s, 1H).

IR (CHCl₃): 2923, 2851, 1675, 1607, 1582, 1482, 1467, 1398, 1379 cm⁻¹.

EXAMPLE 182N-[2-methyl-4,6-bis(ethylthio)pyrimidin-5-yl]-2-hexylthiodecanoic amide

The title compound was prepared in 52% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.19-1.84 (c, 27H); 2.0 (m, 1H); 2.57(s, 3H); 2.75 (t, 2H); 3.15 (q, 4H); 3.44 (t, 1H); 8.04 (s, 1H).

IR (CHCl₃): 2920, 2852, 1680, 1467, 1406, 1359, 1314 cm⁻¹.

EXAMPLE 183 N-(6-methoxyquinolin-5-yl)-2-heptylnonanoic amide

The title compound was prepared in 20% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.88 (m, 6H); 1.18-1.84 (c, 24H); 2.41 (m, 1H); 3.97(s, 3H); 7.13 (s, 1H); 7.36 (q, 1H); 7.5 (d, 1H); 8.04 (t, 2H); 8.78 (m,1H).

IR (CHCl₃): 2921, 2850, 1686, 1596, 1570, 1465, 1322, 1266 cm⁻¹.

EXAMPLE 184 N-(2,4,6-trimethoxyphenyl)-2-heptylnonanoic amide

The title compound was prepared in 72% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.88 (m, 6H); 1.18-1.8 (c, 24H); 2.2 (m, 1H); 3.77 (s,6H); 3.79 (s, 3H); 6.13 (s, 2H); 6.38 (s, 1H).

IR (CHCl₃): 2921, 2850, 1677, 1598, 1505, 1465, 1437, 1413, 1153, 1131cm⁻¹.

EXAMPLE 185 N-(6-methoxyisoquinolin-5-yl)-2-heptylnonanoic amide

The title compound was prepared in 21% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.88 (m, 6H); 1.18-1.85 (c, 24H); 2.41 (m, 1H); 3.98(s, 3H); 7.09 (s, 1H); 7.37 (d, 1H); 7.52 (b, 1H); 7.91 (d, 1H); 8.44(b, 1H); 9.13 (b, 1H).

IR (CHCl₃): 2922, 2850, 1685, 1625, 1465, 1381, 1324, 1279, 1268 cm⁻¹.

EXAMPLE 186 N-(4,6-dimethoxypyrimidin-5-yl ]-2-heptylnonanoic amide

The title compound was prepared in 53% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.18-1.8 (c, 24H); 2.24 (m, 1H); 3.97(s, 6H); 8.32 (s, 1H).

IR (CHCl₃): 2921, 2851, 1686, 1583, 1487, 1463, 1408, 1400, 1312, 1121cm⁻¹.

EXAMPLE 187N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-heptylnonanoic amide

The title compound was prepared in 48% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.17-1.82 (c, 24H); 2.28 (m, 1H); 2.4(s, 3H); 2.48 (s, 3H); 2.50 (s, 3H); 6.53 (s, 1H); 6.63 (s, 1H).

IR (CHCl₃): 2921, 2851, 1686, 1560, 1460, 1338 cm⁻¹.

EXAMPLE 188N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2-heptylnonanoic amide

The title compound was prepared in 35% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (m, 6H); 1.18-1.8 (c, 24H); 2.27 (m, 1H); 2.49(s, 6H); 2.59 (s, 3H); 6.46 (s, 1H).

IR (CHCl₃): 2920, 2850, 1691, 1505, 1462, 1431, 1406, 1360, 1300 cm⁻¹.

EXAMPLE 189N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2,2-dimethyldodecanoicamide

The title compound was prepared in 49% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.67 (c) and 1.32 (s) (total 24H);2.39 (s, 3H); 2.48 (s, 3H); 2.50 (s, 3H); 6.63 (s, 1H); 6.72 (s, 1H).

IR (CHCl₃): 2920, 2850, 1678, 1559, 1459, 1338 cm⁻¹.

EXAMPLE 190 N-(2,4-bis(methylthio)pyridin-3-yl]-2,2-dimethyldodecanoicamide

The title compound was prepared in 40% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.2-1.68 (c) and 1.33 (s) (total 24H);2.41 (s, 3H); 2.51 (s, 3H); 6.79 (s, 1H); 6.82 (d, 1H); 8.25 (d, 1H).

IR (CHCl₃): 2920, 2850, 1679, 1553, 1462, 1370 cm⁻¹.

EXAMPLE 191N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2,2-dimethyldodecanoicamide

The title compound was prepared in 23% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.2-1.68 (c) and 1.31 (s) (total 24H);2.49 (s, 6H); 2.59 (s, 3H); 6.65 (s, 1H).

IR (CHCl₃): 2923, 2849, 1683, 1510, 1467, 1407, 1362, 1301 cm⁻¹.

EXAMPLE 192 N-[4,6-bis(methylthio)pyrimidin-5-yl]-2,2-dimethyldodecanoicamide

The title compound was prepared in 43% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.2-1.68 (c) and 1.32 (s) (total 24H);2.51 (s, 6H); 6.74 (s, 1H); 8.64 (s, 1H).

IR (CHCl₃): 2924, 2851, 1688, 1522, 1468, 1406, 1359 cm⁻¹.

EXAMPLE 193 N-(6-methylthioquinolin-5-yl)-2,2-dimethyldodecanoic amide

The title compound was prepared in 4% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.2-1.78 (c) and 1.42 (s) (total 24H);2.55 (s, 3H); 7.44 (m, 2H); 7.66 (d, 1H); 8.07 (d, 1H); 8.13 (d, 1H);8.83 (m, 1H).

IR (CHCl₃): 2921, 2851, 1677, 1565, 1463, 1375 cm⁻¹.

EXAMPLE 194 N-[2,4-bis(ethylthio)-6-methylpyridin-3-yl]-tetradecanoicamide

The title compound was prepared in 68% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.19-1.62 (c, 26H); 1.76 (m, 2H); 2.39(t, 2H); 2.46 (s, 3H); 2.91 (q, 2H); 3.15 (q, 2H); 6.52 (s, 1H), 6.68(s, 1H).

IR (CHCl₃): 2920, 2850, 1687, 1556, 1460 cm⁻¹.

EXAMPLE 195

N-(2,4-bis(methylthio)-6-methylpyridin-3-yl]-tetradecanoic amide

The title compound was prepared in 59% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.82 (c, 22H); 2.40 (s), 2.48 (s),2.50 (s) and 2.37-2.6 (m) (total 11H); 6.50 (s, 1H); 6.64 (s, 1H).

IR (CHCl₃): 2917, 2847, 1693, 1570, 1472 cm⁻¹.

EXAMPLE 196 N-[4,6-bis(methylthio)pyrimidin-5-yl]-tetradecanoic amide

The title compound was prepared in 76% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.2-1.62 (c, 20H); 1.76 (m, 2H); 2.41(t, 2H); 2.52 (s, 6H); 6.51 (s, 1H); 8.65 (s, 1H).

IR (CHCl₃): 2917, 2847, 1690, 1511, 1459, 1405, 1355 cm⁻¹.

EXAMPLE 197 N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]tetradecanoicamide

The title compound was prepared in 78% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.19-1.61 (c, 20H); 1.75 (m, 2H); 2.40(t, 2H); 2.49 (s, 6H); 2.59 (s, 3H); 6.45 (s, 1H).

IR (CHCl₃): 2917, 2847, 1689, 1460, 1406, 1357 cm⁻¹.

EXAMPLE 198 N-(6-methylthioquinolin-5-yl]tetradecanoic amide

The title compound was prepared on 31% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.2-1.6 (c, 20H); 1.84 (m, 2H); 2.54 (s)and 2.55 (t)(total 5H); 7.18 (s, 1H); 7.40 (m, 1H); 7.64 (d, 1H); 8.06(m, 2H); 8.84 (b, 1H).

IR (CHCl₃): 2919, 2849, 1683, 1565, 1464, 1377 cm⁻¹.

EXAMPLE 199 N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]pentadecanoicamide

The title compound was prepared in 53% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.81 (c, 24H), 2.4 (t, 2H); 2.5 (s,6H), 2.6 (s, 3H); 6.44 (s, 1H).

IR (CHCl₃): 2918, 2847, 1689, 1460, 1425, 1405 cm⁻¹.

EXAMPLE 200 N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]pentadecanoicamide

The title compound was prepared in 68% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.82 (c, 24H); 2.40 (s+t, 5H); 2.51(s, 3H); 6.52 (s, 1H); 6.63 (s, 1H).

IR (CHCl₃): 2921, 2849, 1686, 1612, 1559, 1459 cm⁻¹.

EXAMPLE 201 N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]hexadecanoicamide

The title compound was prepared in 78.2% yield according to theprocedure of Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.49 (c, 22H), 1.57 (m, 2H); 1.75(m, 2H); 2.39 (t, 2H); 2.49 (s, 6H); 2.59 (s, 3H); 6.46 (s, 1H).

IR (CHCl₃): 2919, 2849, 1688, 1459, 1406, 1358 cm⁻¹.

EXAMPLE 202 N-[4,6-bis(ethylthio)pyrimidin-5-yl]hexadecanoic amide

The title compound was prepared in 70% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.5 (c, 28H); 1.58 (m, 2H); 1.76(m, 2H); 2.4 (t, 2H); 3.15 (q, 4H); 6.49 (s, 1H); 8.61 (s, 1H).

IR (CHCl₃): 2918, 2848, 1692, 1460, 1404, 1356 cm⁻¹.

EXAMPLE 203 N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]hexadecanoicamide

The title compound was prepared in 8.6% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.84 (c, 26H); 2.39 (s+t, 5H); 2.48(s, 3H); 2.5 (s, 3H); 6.5 (s, 1H); 6.64 (s, 1H).

IR (CHCl₃): 2921, 2849, 1690, 1612, 1560, 1460 cm⁻¹.

EXAMPLE 204 N-[4,6-bis(methylthio)pyrimidin-5-yl]hexadecanoic amide

The title compound was prepared in 58.8% yield according to theprocedure of Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.49 (c, 22H); 1.57 (m, 2H); 1.76(m, 2H); 2.41 (t, 2H); 2.51 (s, 6H); 6.54 (s, 1H); 8.65 (s, 1H).

IR (CHCl₃): 2920, 2849, 1696, 1521, 1465, 1407, 1358 cm⁻¹.

EXAMPLE 205 N-(4,6-bis(methylthio)pyrimidin-5-yl]-(Z)-9-octadecenoicamide

The title compound was prepared in 61% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.17-1.5 (c, 18H); 1.59 (m, 2H); 1.76(m, 2H); 2.0 (c, 4H); 2.41 (t, 2H); 2.51 (s, 6H); 5.34 (m, 2H); 6.56 (s,1H); 8.65 (s, 1H).

IR (CHCl₃): 2920, 2850, 1693, 1515, 1465, 1407, 1358 cm⁻¹.

EXAMPLE 206N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-(Z)-9-octadecenoic amide

The title compound was prepared in 55% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.68 (c, 20H); 1.77 (m, 2H); 2.0(c, 4H); 2.39 (s +t, 5H); 2.47 (s, 3H); 2.49 (s, 3H); 5.34 (m, 2H); 6.51(s, 1H); 6.63 (s, 1H).

IR (CHCl₃): 2918, 2850, 1686, 1560, 1460, 1339 cm⁻¹.

EXAMPLE 207 N-[4,6-bis(ethylthio)pyrimidin-5-yl]-(Z)-9-octadecenoicamide

The title compound was prepared in 52.3% yield according to theprocedure of Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.19-1.5 (c, 24H); 1.58 (m, 2H); 1.76(m, 2H); 2.01 (c, 4H); 2.40 (t, 2H); 3.15 (q, 4H); 5.34 (m, 2H); 6.5 (s,1H); 8.61 (s, 1H).

IR (CHCl₃): 2920, 2850, 1691, 1508, 1460, 1405, 1355 cm⁻¹ .

EXAMPLE 208N-[2-methyl-4,6-bis(ethylthio)pyrimidin-5-yl]-(Z)-9-octadecenoic amide

The title compound was prepared in 66.7% yield according to theprocedure of Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.5 (c, 24H); 1.58 (m, 2H); 1.75(m, 2H); 2.01 (c, 4H); 2.38(t, 2H); 2.57 (s, 3H), 3.14 (q, 4H); 5.34 (m,2H); 6.41 (s, 1H).

IR (CHCl₃): 2919, 2849, 1690, 1459, 1407, 1357, 1312 cm⁻¹.

EXAMPLE 209 N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-(Z)-9-octadecenoic amide

The title compound was prepared in 55% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.48 (c, 18H); 1.58 (m, 2H); 1.76(m, 2H); 2.0 (c, 4H); 2.39 (t, 2H); 2.49 (s, 6H); 2.59 (s, 3H); 5.33 (m,2H); 6.46 (s, 1H).

IR (CHCl₃): 2923, 2850, 1692, 1508, 1464, 1429, 1406, 1360 cm⁻¹.

EXAMPLE 210 N-[2,4-bis(methylthio)pyridin-3-yl]- (Z)-9-octadecenoicamide

The title compound was prepared in 43% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.18-1.5 (c, 18H); 1.59 (m, 2H); 1.77(m, 2H); 2.01 (c, 4H); 2.41 (s +t, 5H); 2.51 (s, 3H); 5.34 (m, 2H), 6.57(s, 1H); 6.82 (d, 1H); 8.25 (d, 1H).

IR (CHCl₃): 2920, 2850, 1687, 1552, 1461, 1375 cm⁻¹.

EXAMPLE 211 N-[4,6-bis(methylthio)pyrimidin-5-yl]-2-dodecylthioacetamide

The title compound was prepared in 61% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.22-1.49 (c, 18H); 1.67 (m, 2H); 2.53(s, 6H); 2.74 (t, 2H); 3.41 (s, 2H); 8.3 (s, 1H); 8.67 (s, 1H).

IR (CHCl₃): 2917, 2847, 1688, 1467, 1405, 1355 cm⁻¹.

EXAMPLE 212 N-[4,6-bis(ethylthio)pyrimidin-5-yl]-2-dodecylthioacetamide

The title compound was prepared in 52% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.22-1.5 (c, 24H); 1.67 (m, 2H); 2.74(t, 2H); 3.17 (q, 4H); 3.41 (s, 2H); 8.27 (s, 1H); 8.63 (s, 1H).

IR (CHCl₃): 2918 , 2848, 1687, 1466, 1404 , 1353 cm⁻¹.

EXAMPLE 213N-[2,4-bis[methylthio]-6-methylpyridin-3-yl-2-dodecylthioacetamide

The title compound was prepared in 45% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ 0.87 (t, 3H); 1.18-1.46 (c, 18H); 1.67 (m, 2H); 2.41(s, 3H); 2.49 (s, 3H); 2.51 (s, 3H); 2.76 (t, 2H); 3.41 (s, 2H); 6.66(s, 1H); 8.25 (s, 1H).

IR (CHCl₃): 2918, 2848, 1678, 1561, 1476, 1337 cm⁻¹.

EXAMPLE 214 N-[2-4-bis(methylthio)pyridin-3-yl]-2-dodecylthioacetamide

The title compound was prepared in 24% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.17-1.48 (c, 18H); 1.67 (m, 2H); 2.43(s, 3H); 2.53 (s, 3H); 2.76 (t, 2H); 3.42 (s, 2H); 6.85 (d, 1H); 8.28(d, 1H); 8.34 (s, 1H).

IR (CHCl₃): 2919, 2849, 1683, 1553, 1475, 1432, 1376 cm⁻¹.

EXAMPLE 215N-[2,4-bis(ethylthio)-6-methylpyridin-3-yl]-2-dodecylthioacetamide

The title compound was prepared in 37% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.47 (c, 24H); 1.67 (m, 2H); 2.47(s, 3H); 2.77 (t, 2H); 2.92 (q, 2H); 3.15 (q, 2H); 3.41 (s, 2H); 6.69(s, 1H); 8.24 (s, 1H).

IR (CHCl₃): 2920, 2850, 1680, 1559, 1474, 1337 cm⁻¹.

EXAMPLE 216 N-[2-4-bis(ethylthio)pyridin-3-yl]-2-dodecylthioacetamide

The title compound was prepared in 27% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.18-1.47 (c, 24H); 1.67 (m, 2H); 2.77(t, 2H); 2.95 (q, 2H); 3.18 (q, 2H); 3.42 (s, 2H); 6.88 (d, 1H); 8.25(d, 1H); 8.34 (s, 1H).

IR (CHCl₃): 2920, 2850, 1682, 1551, 1474, 1375 cm⁻¹.

EXAMPLE 217N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-trans-3-nonyl1,2,3,4-tetrahydro-2-naphthoicamide

The title compound was prepared in 7% yield according to the procedureof Example 4A. ¹ H NMR (CDCl₃): δ0.87 (m, 3H); 1.2-1.72 (c, 16H); 2.16(m, 1H); 2.41-2.64 (c), 2.51 (s), 2.60 (s) (total 11H); 2.94-3.28 (c,3H); 6.54 (s, 1H); 7.12 (c, 4H).

IR (CHCl₃): 2900, 2830, 1690, 1460 cm⁻¹.

EXAMPLE 218N-[4,6-bis(methylthio)pyrimidin-5-yl]-3-nonyl-1,2,3,4-tetrahydro-2-naphthoicamide

The title compound was prepared in 8% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (m, 3H); 1.18-1.75 (c, 16H); 2.17 (m, 1H);2.4-2.62 (c), 2.53 (s) (total 8H); 2.93-3.27 (c, 3H); 6.6 (s, 1H); 7.13(c, 4H); 8.66 (s, 1H). IR (CHCl₃): 2900, 2830, 1700, 1610, 1470 cm⁻¹.

EXAMPLE 219N-(2,4,6-trifluorophenyl)-trans-3-nonyl-1,2,3,4-tetrahydro-2-naphthoicamide

The title compound was prepared in 15% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (m, 3H); 1.2-1.74 (c, 16H); 2.14 (m, 1H); 2.5 (m,2H); 2.92-3.25 (c, 3H); 6.73 (m, 3H); 7.11 (m, 2H). IR (CHCl₃): 2918,2850, 1697, 1641, 1608, 1507, 1466, 1445 cm⁻¹.

EXAMPLE 220N-(6-methylthioquinolin-5-yl)-2-nonyl-1,2,3,4-tetrahydro-2-naphthoicamide

The title compound was prepared in 3% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.16-2.06 (c, 17H); 2.38 (m, 1H); 2.47(s, 3H); 2.85-3.15 (c, 3H); 3.35 (d, 1H); 7.18 (m, 5H); 7.37 (s, 1H);7.47 (d, 1H); 7.59 (d, 1H), 7.99 (d, 1H); 8.77 (s, 1H).

EXAMPLE 221N-[4,6-bis(methylthio)pyrimidin-5-yl]-2-nonyl-1,2,3,4-tetrahydro-2-naphthoicamide

The title compound was prepared in 11% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.18-1.67 (c, 15H); 1.91 (m, 2H); 2.24(m, 1H); 2.45 (s, 6H); 2.78-2.96 (c, 2H); 3.07 (m, 1H); 3.28 (d, 1H);6.74 (s, 1H); 7.13 (s, 4H); 8.60 (s, 1H). IR (CHCl₃): 2921, 2849, 1681,1518, 1454, 1406, 1357 cm⁻¹.

EXAMPLE 222N'-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-N-[4-(3-methylbutyl)benzyl]-N-cycloheptylurea

A. 2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate

A solution of 800 mg (4 mmol)2,4-bis(methylthio)-3-amino-6-methylpyridine and 0.4 ml (2.3 mmol)trichloromethyl chloroformate in 20 ml anhydrous dioxane was refluxedunder nitrogen overnight. The reaction mixture was cooled and filteredand the filtrate was concentrated to dryness in vacuo yielding 730 mg ofthe title compound (81% yield) as a tan colored solid.

B.N'-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-N-[4-(3-methylbutyl)benzoyl]-N-cycloheptylurea

A solution of 135 mg (0.6 mmol) isocyanate from Example 225A and 164 mg(0.6 mmol) N-cycloheptyl- [4-(3-methylbutyl) benzylamine in 15 mlmethylene chloride was refluxed under nitrogen overnight. The reactionmixture was cooled to room temperature and concentrated in vacuo. Theresidue was chromatographed on 200 g silica gel, eluting with 7:3hexane/ethyl acetate to yield 140 mg (32% yield) of the title compoundas an off-white solid.

¹ H NMR (CDCl₃): δ0.92 (d, 6H); 1.39-1.74 (c, 13H); 1.98 (m, 2H); 2.37(s, 3H); 2.44 (s, 6H); 2.59 (t, 2H); 4.37 (m, 1H); 4.50 (s, 2H); 5.47(s, 1H); 6.57 (s, 1H); 7.18 (d, 2H); 7.32 (d, 2H). IR (CHCl₃): 2921,2853, 1650, 1560, 1469.

The title compounds of Examples 223-227 were prepared according to theprocedure of Example 222.

EXAMPLE 223N'[2,4-bis(methylthio)-6-methylpyridin-3-yl]-N-[4-(2,2-dimethylpropyl)benzyl]-N-cycloheptylurea

70% yield ¹ H NMR (CDCl₃): δ0.88 (s, 9H); 1.39-1.74 (c, 10H); 1.99 (m,2H); 2.33 (s, 3H); 2.44 (2s, 6H); 2.48 (s, 2H); 4.38 (m, 1H); 4.52 (s,2H); 5.46 (s, 1H); 6.57 (s, 1H); 7.13 (d, 2H); 7.31 (d, 2H). IR (CHCl₃):2922, 2853, 1651, 1561, 1470 cm⁻¹.

EXAMPLE 224 N'-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-N-[4-(3-methylbutyl)benzyl]-N-cycloheptylurea

72% yield. ¹ H NMR (CDCl₃): δ0.92 (d, 6H); 1.40-1.75 (c, 13H), 1.98 (m,2H); 2.44 (s, 6H); 2.55 (s, 3H); 2.60 (t, 2H); 4.37 (m, 1H); 4.51 (s,2H); 5.37 (s, 1H); 7.20 (d, 2H); 7.31 (d, 2H). IR (CHCl₃): 2920, 2853,1651, 1467 cm⁻¹.

EXAMPLE 225N'-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-N-[4-(2,2-dimethylpropyl)benzyl]-N-cycloheptylurea

70% yield. ¹ H NMR (CDCl₃): δ0.89 (s, 9H); 1.39-1.77 (c, 10H); 2.00 (m,2H); 2.42 (s, 6H); 2.48 (s, 2H); 2.55 (s, 3H); 4.39 (m, 1H); 4.51 (s,2H); 5.37 (s, 1H), 7.15 (d, 2H); 7.30 (d, 2H). IR (CHCl₃): 2922, 2852,1653 , 1468, 1413 cm⁻¹.

EXAMPLE 226N'-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-N-[4-(3-methylbutyl)benzyl]-N-heptylurea

43% yield. ¹ H NMR (CDCl₃): δ0.86 (m), 0.92 (d) (total 9H); 1.20-1.72(c, 13H); 2.47 (s, 6H); 2.57 (s), 2.60 (t) (total 5H); 3.34 (t, 2H);4.56 (s, 2H); 5.51 (s, 1H); 7.15 (d, 2H); 7.24 (d, 2H). IR (CHCl₃):2920, 2850, 1659, 1468, 1415 cm⁻¹.

EXAMPLE 227N'[2,4-bis(methylthio)-6-methylpyridin-3-yl[-N-[4-(3-methylbutyl)benzyl]-N-heptylurea

32% yield. ¹ H NMR (CDCl₃): δ0.87 (m), 0.92 (d) (total 9H): 1.19-1.72(c, 13H); 2.37 (s, 3H); 2.46 (s, 3H); 2.48 (s, 3H); 2.59 (t, 2H); 3.34(t, 2H); 4.58 (s, 2H); 5.61 (s, 1H); 6.61 (s, 1H); 7.17 (d, 2H); 7.27(d, 2H).

IR (CHCl₃): 2922, 2852, 1656, 1558, 1467 cm⁻¹.

EXAMPLE 228N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-z-decylcyclopentanecarboxamide

The title compound was prepared in 27.4% yield according to theprocedure of Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.2-1.82 (c, 24H); 2.27 (m, 2H); 2.49(s, 6H); 2.59 (s, 3H); 6.6 (s, 1H). IR (CHCl₃): 2921, 2851, 1681, 1450,1407, 1360 cm⁻¹.

EXAMPLE 229 N-[4,6-bis(methylthio)pyrimidin-5-yl]-2-decylcyclopentanecarboxamide

The title compound was prepared in 20% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.21-1.82 (c, 24H); 2.28 (m, 2H); 2.51(s, 6H); 6.69 (s, 1H); 8.64 (s, 1H). IR (CHCl₃): 2922, 2850, 1682, 1452,1405, 1358 cm⁻¹.

EXAMPLE 230N-[4,6-bis(methylthio)pyrimidin-5-yl]-2-decylindane-2-carboxamide

The title compound was prepared in 33.7% yield according to theprocedure of Example 4A.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.14-1.88 (d, 18H); 2.49 (s, 6H); 3.04(d, 2H); 3.58 (d, 2H); 6.63 (s, 1H); 7.2 (c, 4H); 8.63 (s, 1H). IR(CHCl₃): 2922, 2850, 1687, 1526, 1458, 1407, 1359 cm⁻¹.

EXAMPLE 231N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-methylthiotetradecanoicamide

The title compound was prepared in 66% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.2-1.87 (c, 21H); 2.03 (m, 1H); 2.31(s, 3H); 2.41 (s, 3H); 2.50 (s, 3H); 2.53 (s, 3H), 3.38 (t, 1H); 6.66(s, 1H); 8.05 (s, 1H). IR (CHCl₃): 2919, 2850, 1677, 1559, 1522, 1468,1438 cm⁻¹.

EXAMPLE 232N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2-methylthiotetradecanoicamide

The title compound was prepared in 79% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.21-1.86 (c, 21H); 2.04 (m, 1H), 2.29(s, 3H); 2.52 (s, 6H); 2.62 (s, 3H); 3.37 (t, 1H); 8.0 (s, 1H). IR(CHCl₃): 2918, 2849, 1681, 1465, 1405 cm⁻¹.

EXAMPLE 233N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-ethylthiotetradecanoicamide

The title compound was prepared in 51% yield according to the procedureof Example 4B.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.2-1.7 (c, 23H); 1.8 (m, 1H); 2.06 (m,1H); 2.41 (s, 3H); 2.50 (s, 3H); 2.53 (s, 3H); 2.8 (q, 2H); 3.48 (t,1H); 6.66 (s, 1H); 8.13 (s, 1H). IR (CHCl₃): 2920, 2850, 1675, 1560,1466 cm⁻¹.

EXAMPLE 234 N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2-ethylthiotetradecanoic amide

The title compound was prepared in 51% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ 0.87 (t, 3H); 1.2-1.88 (c, 24H); 2.03 (m, 1H); 2.52(s, 6H); 2.62 (s, 3H); 2.79 (q, 2H); 3.48 (t, 1H); 8.08 (s, 1H). IR(CHCl₃): 2920, 2850, 1679, 1465, 1405 cm⁻¹.

EXAMPLE 235N'[2-methyl-4-6-bis(methylthio)pyrimidin-5-yl]-4,5-dimethyl-trans-2-heptylcyclohex-4-enecarboxamide

The title compound was prepared in 31% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.16-2.48 (c, 24H); 2.5 (s, 6H); 2.59(s, 3H); 6.56 (s, 1H).

IR (CHCl₃): 2918, 2850, 1687, 1458, 1406, 1360 cm⁻¹.

EXAMPLE 236N-[4,6-bis(methylthio)pyrimidin-5-yl]-4,5-dimethyl-trans-2-heptylcyclohex-4-enecarboxamide

The title compound was prepared in 27% yield according to the procedureof Example 4A.

¹ H NMR (CDCl₃): δ0.87 (t, 3H); 1.17-2.49 (c, 24H); 2.52 (s, 6H); 6.64(s, 1H); 8.65 (s, 1H). IR (CHCl₃): 2920, 2852, 1690, 1458, 1405, 1356cm⁻¹.

EXAMPLE 237N-(6-methoxyisoquinolin-5-yl)-4,5-dimethyl-trans-2-heptylcyclohex-4-enecarboxamide

The title compound was prepared in 8.5% yield according to the procedureof Example 4.

¹ H NMR (CDCl₃): δ0.86 (t, 3H); 1.14-2.5 (c, 24H); 3.99 (s, 3H); 7.17(s, 1H); 7.39 (d, 1H); 7.52 (m, 1H); 7.94 (d, 1H); 8.45 (m, 1H); 9.14(m, 1H). IR (CHCl₃): 2920, 2850, 1678, 1625, 1464, 1382 cm⁻¹.

EXAMPLE 238 3-Amino-2,4-bis(methylthio)-6-methylpyridine

To a solution of 15.5 g (0.22 mol) sodium methanethiolate in 200 mlmethanol was added slowly with stirring under nitrogen a solution of20.8 g (0.1 mol) 3-nitro-2,4-dichloro-6-methylpyridine in 150 mlmethanol. A precipitate formed and the mixture was stirred overnight atroom temperature. The mixture was then filtered and the solid was washedfirst with methanol and then with water.3-Nitro-2,4-bis(methylthio)-6-methylpyridine (18.9 g, 82% yield) wasobtained as a yellow solid, mp 172°-176° C.

¹ H NMR (CDCl₃): δ 2.45 (s, 3H); 2.51 (s, 3H); 2.55 (s, 3H); 6.77 (s,1H).

A mixture of 18.9 g (0.082 mol)3-nitro-2,4-bis(methylthio)-6-methylpyridine and 18.9 g Raney nickel in600 ml. 1,4-dioxane and 300 ml methanol was shaken with hydrogen (15psi) in a Parr hydrogenation apparatus for 3.5 hr. The catalyst wasfiltered and the filtrate was concentrated to dryness in vacuo. Thesolid residue was chromatographed on silica gel (650g), eluting with 9:1hexane/ethyl acetate to yield 14.0 g. (85% yield) of the title compoundas an off-white solid.

NMR (CDCl₃): δ 2.42 (s, 3H); 2.44 (s, 3H); 2.59 (s, 3H); 4.02 (b, 2H);6.72 (s, 1H).

The title compounds of Examples 239-241 were prepared according to theprocedure of Example 238.

EXAMPLE 239

A. 3-Amino-2,4-bis(methylthio) pyridine

(79% yield) ¹ H NMR (CDCl₃): δ 2.45 (s, 3H); 2.60 (s, 3H); 4.14 (b, 2H);6.88 (d, 1H); 7.90 (d, 1H).

EXAMPLE 240

B. 3-Amino-2,4-bis(ethylthio)pyridine

(86% yield) ¹ H NMR (CDCl₃): δ 1.29 (t, 3H); 1.34 (t, 3H); 2.91 (q, 3H);3.21 (q, 3H); 4.30 (b, 2H); 6.93 (d, 1H); 7.86 (d,1H).

EXAMPLE 241

C. 3-Amino-2,4-bis(ethyl)-6-methylpyridine

(86% yield) ¹ H NMR (CDCl₃): δ 1.30 (t, 3H); 1.32 (t, 3H); 2.40 (s, 3H);2.90 (q, 2H); 3.18 (q, 2H); 4.18 (b,2H); 6.79 (s, 1H).

EXAMPLE 242 (2S)-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hexylthiodecanoic amide

(S)-(-)-2-Hexylthiodecanoic, prepared according to Example IB, wascoupled with 3-amino-2,4-bis(methylthio)-6-methylpyridine by theprocedure of Example 4B to yield the title compound in 55% yield;[α]_(D) ^(RT) =-59° (CH₃ OH). A sample recrystallized from petroleumether had mp 81°-83° C. and [α]_(D) ^(RT) =-66° (CH₃ OH).

EXAMPLE 243(2R)-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 30.1% yield according to a proceduresimilar to that of Example 243. A sample recrystallized from petroleumether had mp 80°-82° C. and [α]_(D) ^(RT) =+61.7° (CH₃ OH).

EXAMPLES 244(2S)-N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 47.2% yield by the coupling ofS-(-)-2-hexylthiodecanoic acid with5-amino-4,6-bis(methylthio)-2-methylpyrimidine according to theprocedure of Example 4A. A sample recrystallized from diethyl ether hadmp 98°-100° C. and [α]_(D) ^(RT) =-62° (CH₃ OH).

EXAMPLE 245(2R)-N-[2-methyl-4,6-bis(methylthio)pyrimidin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared in 50.3% yield by a procedure similar tothat of Example 245. A sample recrystallized from diethyl ether had mp95°-97.5° C. and [α]_(D) ^(RT) =+56.0° (CH₃ OH).

EXAMPLE 246 (2S)-N-[6-(methylthio)quinolin-5-yl]-2-hexylthiodecanoicamide

The title compound was prepared by the recoupling ofS-(-)-2-hexylthio-decanoic acid with 5-amino-6-methylthioquinoline(Example 34) according to the procedure of Example 25. M.p.: 114°-115°C.

Optical rotation: [α]_(D) ²³ =-52° (in CDCl₃). Analytical analysis ofenantiomeric purity was accomplished using a Chiracel OD HPLC column.

EXAMPLE 247 N-(6-methylthioquinolin-5-yl)-2-bromodecanamide

To a stirred solution of 2-bromodecanoic acid (184 mg, 0.73 mmol) in CH₂Cl₂ (3.0 ml) was injected by syringe oxalyl chloride (0.06 ml, 105 mol%) and then DMF (1 drop). After stirring at room temperature for 1 hour,N-methyl morpoline (0.24 ml, 300 mol %) was added. To this mixture wasinjected a solution of 5-amino-6-methylthioquinoline (139 mg, 100 mol%)in CH₂ Cl₂ (2.0 ml). After stirring at room temperature for anadditional 30 min. the reaction mixture was diluted with CH₂ Cl₂ (30ml), poured over 1.0M H₃ PO₄ (100 ml), and extracted with CH₂ Cl₂ (3×30ml). The combined extracts were dried (Na₂ SO₄), evaporated, andchromatographed using 1% triethylamine: ethyl acetate as eluants to givethe title compound (192 mg, 62% yield).

IR (CDCl₃) 3350, 2930-2820, 1710 cm⁻¹. ¹ H NMR (CDCl₃) δ8.84 (m, 1H);8.05 (m, 3H); 7.63 (d, 1H, J=9.4 Hz); 7.41 (dd, 1H, J=3.7, 8.5 Hz); 4.57(dd, 1H, J=5.5, 8.3 Hz); 2.54 (s, 3H); 2.25 (m, 1H); 2.15 (m, 1H); 1.58(m, 2h); 1.26 (m, 10H); 0.85 (m, 3H).

EXAMPLE 248 N-(6-methylthioquinolin-5-yl)-2-hexylaminodecanamide

A mixture of N-(6-methylthioquinolin-5-yl)-2-bromodecanamide (200 mg,0.47 mmol) and n-hexylamine (10 ml) was heated at 120° C. for 1 hour,cooled to room temperature, and chromatographed using1:24:25/triethylamine:ethyl acetate:hexane as eluants to give the titlecompound as a pink oil (184 mg, 88% yield).

IR (CHCl₃) 3280, 2940-2860, 1680 cm. ¹ H NMR (CDCl₃) δ9.38 (s, 1H); 8.80(m, 1H); 7.97 (m, 2H); 7.62 (d, 1H, J=8.8 Hz); 7.36 (dd, 1H, J=4.3, 8.6Hz); 3.28 (dd, 1H, J=4.7, 8.6 Hz); 2.86 (m, 1H), 2.78 (m, 1H); 2.51 (s,3H); 1.98 (m, 1H); 1.74 (m, 1H); 1.56 (m, 5H); 1.30 (m, 16H); 0.86 (m,6H). Mass spectrum m/e (relative intensity): M⁺ 444.30 (82), 226.40(100). Anal. Calc'd for C₂₆ H₄₁ N₃ OS: C, 70.4; H, 9.3; N, 9.5; Found:C, 70.9; H, 9.4; N, 9.5.

EXAMPLE 249N-(6-methylthioquinolin-5-yl)-2-N,N-[(acyl)(hexyl)]aminodecanamide

To a stirred solution ofN-(6-methylthioquinolin-5-yl)-2-hexylaminodecanamide (200 mg, 0.45 mmol)pyridine (10 ml) was added in one portion acetic anhydride (2.0 ml).After stirring at room temperature for 1 hour, the mixture was pouredover 1.0M H₃ PO₄ (200 ml) and extracted with CH₂ Cl₂ (3×100 ml). Thecombined extracts were dried (Na₂ SO₄), evaporated, and chromatographedusing ethyl acetate as eluant to give the title compound (200 mg, 91%yield).

¹ H NMR (CDCl₃) δ 8.81 (d, 1H, J=2.9 Hz); 8.66 (s, 1H); 8.01 (d, 1H,J=6.7 Hz); 8.00 (d, 1H, J=2.0 Hz); 7.60 (d, 1H, J=9.1 Hz); 7.36 (dd, 1H,J=4.2, 8.6 Hz); 4.95 (m, 1H), 3.33 (t, 2H, J=8.3 Hz); 2.50 (s, 3H); 2.24(s, 3H); 2.15 (m, 1H); 1.88 (m, 1H); 1.66 (m, 2H); 1.25 (m, 18H); 0.86(m, 6H). Mass spectrum m/e (relative intensity): M⁺ 486.3 (87), 296.3(62), 268.3 (32), 226.3 (100).

EXAMPLE 250N-(6-methylthioquinolin-5-yl)-2-N,N-[(hexyl)(methylsulfonyl)]aminodecanamide

To a stirred solution ofN-(6-methylthioquinolin-5-yl)-2-hexylaminodecanamide (200 mg, 0.45 mmol)and triethylamine (0.19 ml, 300 mol%) in CH₂ Cl₂ (5 ml) was addeddropwise a mixture of methanesulfonyl chloride (0.038 ml, 110 mol%) inCH₂ Cl₂ (5 ml) at 0° C. After stirring at 0° C. for 30 min, the reactionmixture was allowed to warm to room temperature. After stirring at roomtemperature for 3 hours, the mixture was chromatographed using 1%triethylamine:ethyl acetate as eluants to give the title compound (120mg, 51% yield).

¹ H NMR (CDCl₃) δ 8.84 (s, 1H); 8.31 (s, 1H); 8.13 (d, 1H, J=8.4 Hz);8.05 (d, 1H, J=9.0 Hz); 7.64 (d, 1H, J=9.0 Hz); 7.42 (dd, 1H, J=4.2, 8.5Hz); 4.51 (t, 1H, J=7.4 Hz); 3.40 (m, 3H); 3.01 (s, 3H); 2.54 (s, 3H);2.19 (m, 1H); 1.77 (m, 2H); 1.28 (m, 18H); 0.87 (m, 6H). Mass spectrumm/e (relative intensity): M⁺ 522.3 (100).

EXAMPLE 251N-(6-methylthioquinolin-5-yl)-2-N,N-[(benzenesulfonyl)-hexyl)]aminodecanamide

The title compound was prepared according to the procedure of Example250.

¹ H NMR (CDCl₃) δ 8.85 (s, 1H); 8.50 (s, 1H); 8.22 (d, 1H, J=8.4 Hz);8.11 (d, 1H, J=9.0 Hz); 7.91 (m, 2H); 7.68 (d, 1H, J=9.0 Hz); 7.59 (m,3H); 7.45 (dd, 1H, J=4.1, 8.5 Hz); 4.45 (t, 1H, J=7.3 Hz); 3.49 (m, 2H);3.28 (m, 1H); 2.56 (s, 3H); 2.06 (m, 1H); 1.76 (m, 2H); 1.20 (m, 18H);0.86 (m, 6H). Mass spectrum m/e (relative intensity): M⁺ 584.4 (100).

EXAMPLE 252N-[4-dimethylamino-6-(cyano)(hexyl)aminopyrimidin-5-yl]-2-N,N-[(cyano)(hexyl)]aminodecanamide

To a stirred solution ofN-[4-dimethylamino-6-hexylaminopyrimidin-5-yl)-2-hexylaminodecanamide(200 mg, 0.41 mmol), N-methyl morpholine (5 drops) in THF (5 ml) wasadded in one portion solid cyanobromide (95 mg, 220 mol%). Afterstirring at room temperature for 1 hour the mixture was chromatographedusing 1:1/ethyl acetate:hexane as eluants to give the title compound(130 mg, 59% yield).

IR (CHCl₃) 3450, 3000-2800, 2200, 1740, 1650, 1600 cm⁻¹. ¹ H NMR (CDCl₃)δ8.24 (s, 1H); 4.22 (m, 1H); 4.07 (m, 2H); 3.40 (m, 2H); 3.18 (m, 1H);2.97 (s, 3H); 2.96 (s, 3H); 2.12 (m, 1H); 1.94 (m, 1H); 1.64 (m, 2H);1.49 (m, 2H); 1.28 (m, 24H); 0.86 (m, 8H). Mass spectrum m/e (relativeintensity): M⁺ 542 (100); Anal. calc'd for C₃₀ H₅₂ N₈ O: C, 66.6; H,9.7; N, 20.7; Found: C, 66.4; H, 9.8; N, 20.6.

EXAMPLE 253 N-(6-methylthioisoquinolin-5-yl)-2-(hexylthio)decanamide

Commercially available 4-chlorobenzaldehyde (10 g) was cyclized withaminoacetaldehyde diethyl acetal according to the procedure ofHendrickson, et al., J. Org. Chem., 48, 3344 (1983), to give6-chloroisoquinoline (600 mg). Nitration of the obtained product usingthe procedure of Campbell et al., J. Am. Chem. Soc., 68, 1559 (1946)gave 6-chloro-5-nitroisoquinoline (700 mg). Substitution of 6-chloro forthiomethoxide according to the procedure of Massie, Iowa State Coll. J.Sci., 21, 41 (1946) (Ca 41:3033 g) gave 6-methylthio-5-nitroisoquinoline(632 mg). This material (200 mg) was reduced using stannous chloride(2.0 g) and concentrated hydrochloric acid (30 ml) to give5-amino-6-(methylthio) isoquinoline (143 mg). This material (140 mg) wascoupled with 2-hexylthiodecanoic acid (prepared according to theprocedures described in Examples 1 and 3) using the procedure describedin Example 25 to give the title compound (80 mg).

¹ H NMR (CDCl₃) δ 9.16 (s, 1H); 8.59 (s, 1H); 8.48 (d, 1H, J=5.9 Hz);7.88 (d, 1H, J=8.7 Hz); 7.48 (m, 2H); 3.54 (dd, 1H, J=6.3, 8.1 Hz); 2.79(t, 2H, J=7.4 Hz); 2.55 (s, 3H); 2.12 (m, 1H); 1.88 (m, 1H); 1.65 (m,4H); 1.30 (m, 16 H); 0.88 (m, 6H). Mass spectrum m/e (relativeintensity): M⁺ 461.3; Anal. calc'd for C₂₆ H₄₀ N₂ OS₂ : C, 67.8; H, 8.8;N, 6.1; Found: C, 67.9; H, 8.9; N, 6.1.

EXAMPLE 254N-[4,6-bis(dimethylamino)pyrimidin-5-yl]-cis-9-octadecenamide

5-Amino-4,6-bis(dimethylamino)pyrimidine (prepared by reactingcommercially available 4,6-dichloro-5-nitro pyrimidine with excessdimethylamine followed by reduction of the nitro group according to theprocedure of Jacobs et al., J. Am. Chem. Soc., 42, 2278 (1920)) wascoupled with oleoyl chloride using the procedure described in Example 4to give the title compound.

¹ H NMR (CDCl₃) δ 8.15 (s, 1H); 7.52 (s, 1H); 5.31 (m, 2H); 3.06 (s,6H); 2.99 (s, 6H); 1.98 (m, 4H); 1.72 (m, 2H); 1.24 (m, 22H); 0.85 (m,3H). Mass spectrum m/e (relative intensity): M⁺ 446 (100), 182 (47).

EXAMPLE 255N-(4-dimethylamino-6-chloropyrimidin-5-yl)-cis-9-octadecenamide

5-Amino-4-(dimethyl)amino-6-chloropyrimidine (prepared by reactingcommercially available 5-amino-4,6-dichloropyrimidine with excessdimethylamine) was coupled with oleoyl chloride according to theprocedure described in Example 4 to give the title compound.

IR (CHCl₃) 3400, 3000-2800, 1700, 1570 cm⁻¹. ¹ H NMR (CDCl₃) δ8.23 (s,1H); 6.82 (s, 1H); 5.34 (m, 2H); 3.15 (s, 6H); 2.40 (t, 2H, J=7.6 Hz);2.01 (m, 4H); 1.73 (m, 2H); 1.25 (m, 20H); 0.86 (m, 3H). Mass spectrumm/e (relative intensity): M⁺ 437 (100). Anal. Calc'd for C₂₄ H₄₁ N₄ OCl:C, 66.0; H, 9.5; N, 12.8. Found: C, 65.7; H, 9.5; N, 12.9.

EXAMPLE 256N-(4-dimethylamino-6-methylthiopyrimidin-5-yl)-cis-9-octadecenamide

5-Amino-4-dimethylamino-6-methylthiopyrimidine (prepared by reacting5-amino-4-dimethylamino-6-chloropyrimidine with sodium thiomethoxide)was coupled with oleoyl chloride using the procedure described inExample 4 to give the title compound.

IR (KBr) 3220, 3000-2800, 1650, 1550 cm⁻¹. ¹ H NMR (CDCl₃) 8.32 (s, 1H);6.68 (s, 1H); 5.33 (m, 2H); 3.09 (s, 6H); 2.45 (s, 3H); 2.37 (t, 2H,J=7.7 Hz); 2.00 (m, 4H); 1.72 (m, 2H); 1.25 (m, 20H); 0.86 (m, 3H). Massspectrum m/e (relative intensity): M⁺ 449.4 (62), 185 (100). Anal.Calc'd for C₂₅ H₄₄ N₄ OS: C, 66.9; H, 9.9; N, 12.5. Found: C, 67.3; H,10.2; N, 12.4.

EXAMPLE 257 N-(4-bromoisoquinolin-5-yl)-2-hexylthiodecanamide

5-Amino-4-bromoisoquinoline (prepared according to the process describedby Gordon et al., J. Het. Chem., 4, 410 (1967)) was coupled with2-hexylthiodecanoic acid (prepared by the procedures described inExamples 1 and 3) using the procedure described in Example 25 to givethe title compound.

IR (CHCl₃) 3320, 3000-2800, 1680 cm⁻¹. ¹ H NMR (CDCl₃) δ10.10 (s, 1H);9.11 (s, 1H); 8.68 (s, 1H); 8.51 (d, 1H, J=7.7 Hz); 7.82 (dd, 1H, J=1.2,8.1 Hz); 7.67 (t, 1H, J=8.0 Hz); 3.50 (t, 1H, J=7.3 Hz); 2.60 (t, 2H, J=7.3 Hz); 2.05 (m, 1H); 1.82 (m, 1H); 1.59 (m, 4H); 1.24 (m, 16H); 0.85(m, 6H). Mass spectrum m/e (relative intensity): M⁺ 495 (50), 415 (100).Anal. calc'd for C₂₅ H₃₇ N₂ OSBr: C, 60.8; H, 7.6; N, 5.7. Found: C,61.0; H, 7.5; N, 5.7.

EXAMPLE 258 N-(4-methylthioisoquinolin-5-yl)-2-hexylthiodecanamide

5-Amino-4-bromoisoquinoline (prepared according to the process describedby Gordon et al., J. Het. Chem,, 4, 410 (1967)) was allowed to reactwith sodium thiomethoxide according to the procedure of Massie, IowaState Coll. J. Sci., 21, 41 (1946) (Ca. 41: 3044 g) to give5-amino-4-methylthioisoquinoline. This material was coupled with2-hexylthiodecanoic acid (prepared by the procedures described inExamples 1 and 3) using the procedure described in Example 25 to givethe title compound.

IR (KBr) 3230, 3000, 2800, 1660 cm⁻¹. ¹ H NMR (CDCl₃) δ11.65 (s, 1H);9.12 (s, 1H); 8.84 (d, 1H, J=7.8 Hz); 8.63 (s, 1H); 7.76 (dd, 1H, J=1.2,8.1 Hz); 7.64 (t, 1H, J=8.0 Hz); 3.44 (t, 1H, J=7.5 Hz); 2.65 (m, 2H);2.53 (s, 3H); 2.03 (m, 1H); 1.83 (m, 1H); 1.59 (m, 4H); 1.24 (m, 16H);0.84 (m, 6H). Mass spectrum m/e (relative intensity): M⁺ 461.3 (100).Anal. calc'd for C₂₆ H₄₀ N₂ OS₂ : C, 67.8; H, 8.8; N, 6.1. Found: C,68.0; H, 8.9; N, 6.0.

EXAMPLE 259 N-(4-bromoisoquinolin-5 -yl)-cis-9-octadecenamide

5-Amino-4-bromoisoquinoline (prepared according to the process describedby Gordon et al., J. Het. Chem., 4, 410 (1967)) was coupled with oleoylchloride using the procedure described in Example 4, to give the titlecompound.

IR (CHCl₃) 3420, 3000-2800, 1695 cm⁻¹. ¹ H NMR (CDCl₃) δ9.10 (s, 1H);9.04 (s, 1H); 8.65 (s, 1H); 8.42 (d, 1H, J=7.3 Hz); 7.80 (d, 1H, J=8.0Hz); 7.65 (t, 1H, J=7.9 Hz); 5.33 (m, 2H); 2.49 (t, 2H, J=7.3 Hz); 2.00(m, 3H); 1.80 (m, 2H); 1.25 (m, 21H); 0.86 (m, 3H). Mass spectrum m/e(relative intensity): M⁺ 489.3 (37), 461.3 (14), 407.3 (100). Anal.calc'd for C₂₇ H₃₉ N₂ OBr: C, 66.8; H, 8.1; N, 5.8. Found: C, 67.3; H,8.4; N, 5.6.

EXAMPLE 260 N-(4-dimethylamino-6-hexylaminopyrimidin-5-yl)-2-hexylaminodecanamide

5-Amino-4-(dimethyl)amino-6-chloropyrimidine (prepared as described inExample 257) was coupled with 2-bromodecanoic acid using the proceduredescribed in Example 249, followed by the addition of n-hexylamine asdescribed in Example 250 to give the title compound.

IR (CHCl₃) 3280, 3000-2700, 1660, 1600 cm⁻¹. ¹ H NMR (CDCl₃) δ8.86 (s,1H); 8.20 (s, 1H); 5.47 (t, 1H, J=5.0 Hz); 3.40 (m, 2H); 3.18 (m, 1H);2.88 (s, 6H); 2.66 (m, 2H); 1.85 (m, 1H); 1.44 (m, 31H); 0.86 (m, 8H).Mass spectrum m/e (relative intensity): M⁺ 491.5 (100). Anal. calc'd forC₂₈ H₅₄ N₆ O: C, 68.5; H, 11.1; N, 17.1. Found: C, 68.8; H, 11.3; N,17.5.

EXAMPLE 261 (2S)-Methyl-2hexylthiodecanoate

(2R)-Methyl-2-hydroxydecanoate (202.3 g, 1.00 mol) was dissolved of in 5L of dry acetonitrile. The vessel was flushed with nitrogen and cooledto an internal temperature of -25° C. Triflic anhydride (185 mL, 310 g,1.10 mol) was added slowly followed by triethylamine (TEA) (150 mL, 111g, 1,10 mol) at such a rate that the internal temperature stayed below-20° C. The reaction remained clear and colorless; rapid addition of TEAwill cause coloring. The reaction was stirred for fifteen minutes afterthe TEA addition. Then layer chromatography revealed (eluting with 10:1hexane/ethyl acetate, developing with PMA and heat) that the startingmaterial (R_(f) 0.2) was gone.

Hexanethiol (193 mL, 162 g, 1.30 mol) was added rapidly followed by slowaddition of TEA (181 mL, 131 g, 1.30 mol). The reaction was warmed toroom temperature and stirred for on hour. TLC (eluting with 10:1 hexanesto ethyl acetate revealed (2S)-methyl-2-hexylthiodecanoate at R_(f) 0.5.The acetonnitrile was azeotroped with ethy acetate. The ethyl acetatewas washed with 3 L of water and then with 1 L of brine. The organiclayer was dried with MgSO₄ and concentrated to an oil. The oil wasfiltered through silica gel [Kieselgel 60 (trademark) (230-400 mesh), 15g silica/g crude product], eluted with hexane and flushed with 30:1hexane/ethyl acetate to give (2S)-methyl-2-hexythiodecanoate (295 g,0.97 mol, 97%) as a colorless oil.

[α]_(D) =-72.5° (c=1, MeOH).

¹ H NMR 3.71 (s, 3H), 3.21 (dd, 1H, J=7, 8 Hz), 2.55 (m, 2H), 1.88-1.15(m, 22H), 0.95 (m,6H); ¹³ C NMR 173.46, 52.05, 46.64, 31.81, 31.46,31.37,31.30, 29.30, 29.17, 28.51, 27.38, 22.63, 22.50, 14.06,13.99.Anal. Calcd. for C₁₇ H₃₄ O₂ S: C, 67,50; H, 11.33. Found: C, 67.60; H,11.45%.

EXAMPLE 262 (2S)-2-Hexylthiodecanoic acid

To a 12 L flask equipped with a condenser and overhead stirrer was added(2S)-methyl-2-hexylthiodecanoate (302.5 g, 1.00 mol), and 3 L of dryacetonitrile. To this solution was added sodium iodide (600 g, 4.00 mol)and iodine (25.4 g, 0.10 mol) followed by chlorotrimethylsilane (543 g,635 ml, 5.00 mol). The reaction was heated to an internal temperature of55° C. After 12 hours, an additional portion of chlorotrimethylsilane(130 g, 152 mL, 1.20 mol) was added and heating continued for 8 hours.The reaction was cooled to 0° C., 6 L of hexane was added to separate.The top hexane layer was separated and set aside. The combined CH_(c)CN/water layers were extracted with hexane (2×6 L). The combined hexanelayers were washed with 1 L of water, 0.1M Na₂ S₂ O₃ (2×3 L) and oncewith 3 L of 1:1 brine/water. The combined hexane extracts were driedwith MgSO₄, filtered and concentrated to give (2S)-2-hexlythiodecanoicacid (260 g, 0.90 mol, 90%) a colorless oil.

[α]_(D) =-59.40° (c=1, MeOH.

¹ H NMR δ3.19 (m, 1H), 2.63 (m, 2H), 1.95-1.18 (m, 22H), 0.95 (m, 6H).

(2S)-2-Hexylthiodecanoic acid was purified by formation of thedicyclohexylamine salt. (2S)-2-hexylthiodecanoic acid (0.30 gm, 1.05mmol) was dissolved in 5 ml of CH₃ CN and to this solution was addeddicylohexyl amine (0.19 gm, 1.05 mmol) at room temperature. Afterstirring for 1 hour the salts were collected by filtration andrecrystallized in 5-10 ml of CH₃ CN. Dicyclohexyl-ammonium(2S)-2-hexylthiodecanoate was collected by filtration (0.420 gm, 0.89mmol, 85%).

M.p. 84°-85° C. The salt was cleaved by stirring in 1N HCl and hexanefor 1 hour. The (2S)-2-hexylthiodecanoic acid was recovered byextraction as above.

EXAMPLE 263 (2S)-N-(6-Methylthioquinolin-5-yl)-2-hexylthiodecanoicamide

(2S)-2-hexylthiodecanoic acid (Example 16) (0.89 g, 3.08 mmol) wasdissolved in 15 ml of methylene chloride and cooled to 0° C. A catalyticamount of dimethylformamide (DMF) (0.012ml, 0.15 mmol) was addedfollowed by oxalyl chlorid (0.32 ml, 3.70 mmol). The reaction wasallowed to warm to room temperature and stirred for 1-1.5 hours.N-6-Methylthio-5-quinolinamine (0.616 g, 3.24 mmol) was dissolved in 2ml of pyridine and added dropwise to the reaction. The reaction wasstirred at room temperature for 3 hours. Ethyl acetate (35 ml) was addedand the organic phase was washed with saturated NaHCO₃ (2×10 ml)followed by water (2×10 ml). The ethyl acetate extracts were dried andconcentrated to give crude(2S)-N-(6-methylthioquinolin-5-yl)-2-hexylthiodecanoic amide (2.22 grecovered). (2S)-N-(6-Methylthioquinolin-5-yl)-2-hexylthiodecanoicamidewas recrystallized from acetonitrile (6 ml) to give the pure titlecompound (1.02 g, 2.2 mmol, 72%) as a white solid. M.P. 113,5°-114.5°,[α]_(D) =-73.0° (C=0.7, MeOH; [α]_(D) =-51.6° (C=0.5, CHCl₃). IR (CHCl₃Y) 3652, 3304, 2921, 2851, 1674, 1584, 1566, 1468, 1376, 1311, 1170,969, 866, 823 cm⁻¹ ; ¹³ C NMR 171.96, 149.75, 146.71, 134.26, 131.36,129.51, 128.99, 126.89, 125.63, 121.69, 51.08, 33.08, 32.27, 31.87,31.43, 29.42, 29.30, 29.25, 28.65, 27.78, 22.68, 22.55, 15.73, 14.12,14.03.

Anal. Calcd for C₂₆ H₄₀ N₂ OS₂ : C, 67.78; H, 8.75; Bm 6,08. Found C,67.71; H, 8.82; N, 6.03%. ¹ H NMR 8.84 (dd, 1H, J=2.5, 4.2 Hz), 8.61 (s,1H), 8.04 (t, 2H), J=8.87 Hz, 7.66 (d, 1H, J =8.7 Hz), 7.39 (dd, 1H,J=8.5, 8.7 Hz) 3.52 (dd, 1H, J=6.2, 8.1 Hz) 2.79 (t, 2H, J=7.3 Hz), 2.55(s, 3H), 2.12 (m, 1H), 1.85 (m, 1H), 1.65-1.29 (m, 20H), 0.85 (m, 6h),

EXAMPLE 264 (2)-N-(6-Methylthioquinolin-5-yl)-2-hexylthiodecanoamide

N-6-Methylthio-5-quinolinamine (0.61 g, 3.23 mmol) was dissolved in 20ml of methylene chloride. A solution of AlMe₃ (0.23 ml, 6.46 mmol of2.0M solution in hexane) was added dropwise. The reaction mixture turnedbright red and was stirred at room temperature for 20 minutes.(2S)-methyl-2-hexylthiodecanoate was added in 10 ml of methylenechloride and the reaction heated to a bath temperature of 55° C. After20 hours the reaction was cooled, poured into a saturated aqueoussolution of NaHCO₃ and extracted with ethyl acetate (2×60 ml). Theorganix phase was washed with NaHCO₃ followed by brine, dried over MgSO₄and concentrated to give yellow solids (1.50 gm, 3.25 mmol, 100%). Thesolids were recrystallized from 10 ml of acetonitrile to yield(2S)-N-(6-methylthioquinolin-5-yl)-2-hexythiodecanoamide as a whitesolid (0.58 gm, 1.26 mmol, 39%).

[α]_(D) =-51.74° (c=0.31, CHCl₃). M.p. 101°-102° C. Exact mass (EI)calculatd for C₂₆ H₄₀ N₂ S₂ O: 460.2573. Found: 460.1575.

EXAMPLE 265(2S)-N-2,4[(Methylthio)-6-methyl-3-pyridinyl]-2-phenylthiodecanoamide

N-2,4-(Methylthio)-6-methyl-3pyridinamine (0.117 gm, 0.58 mmol) wasdissolved in 3 ml of methylene chloride and treated with AlMe₃ (0.65 ml,1.28 mmol of 2.0M solution in hexane). This solution was heated to abath temperature of 50°-55° C. and stirred for 1-1.5 hours. Methyl2-phenylthiodecanoate was added to the reaction in 1 ml of methylenechloride. Heating was continued for 5 hours; then the reaction wasallowed to stir at room temperature for 48 hours. The reaction wasslowly poured into saturated NaHCO₃ (5 ml) and extracted with ethylacetate 2×10 ml). The combined organic layers were washed with NaHCO₃(2×5 ml), brined and dried over MgSO₄. Following concentration of thesolvent, the crude oil was recrystallized from 1.5 ml of acetonitrile togive(2S)-N-2,4-[(Methylthio)-6-methyl-3-pyridinyl]2-phenylthiodecanamide(0.104 gm, 0.22 mmol, 39%) as a white solid.

M.p. 102°-104° C.

EXAMPLE 266 (2R)-N-(6-Methylthioquinolin-5-yl)-2-hydroxydecanoamide

(2R)-2Hydroxydecanoic acid (2.3 gm, 12.24 mmol) was dissolved in 70 mlof methylene chloride and [FILL IN NAME] TMSCI (3.42 ml, 26.9 mmol) andcatalytic DMPA were added to the reaction. Pyridine (2.18 ml, 26.9 mmol)was added slowly and the reaction was cooled to 0° C. and 0.4 ml of DMFadded followed by oxalyl chloride (1.28 ml, 14.67 mmol). The reactionwas allowed to warm slowly to room temperature over 1.5 hours. The amine(2.33 gm, 12.24 mmol) was dissolved in 15 ml of pyridine and added tothe reaction. Stirring was continued at room temperature for 6 hours.The reaction was poured into a saturated solution of NaHCO₃ (50 ml) andextracted with ethyl acetate (2×100 ml). The organic layers were washedwith saturated NaHCO₃ (2×50 ml) and brine. The combined ethyl acetatelayers were dried (MgSO₄) and concentrated to give an orange oil (6 gm).This material was dissolved in 75 ml of THF at room temperature and NBu₄NF--3H₂ O (4.64 fm, 14.7 mmol) added and the reaction stirred for 4hours. The reaction was poured into saturate . NaHCO₃ (50 ml) andextracted with ethyl acetate (2×100 ml). The organic phase was washedwith brine, dried (MgSO₄) and concentrated to a waxy solid (6 gm). Thesolid was recrystallized from ethy acetate (50 ml) to give(2R)-N-(-methylthioquinolin-5-yl)-2-hydroxydecanoamide (3.53 gm, 9.79mmol, 80%) as a beige solid.

[α]_(D) =+3.49° (c=0.41, MeOh). M.p. 119°-120° C.

EXAMPLE 267 (2S)-N-(6-Methylthioquinolin-5-yl)-hexylthiodecanoamide

(2R)-N-(6-Methylthioquinolin-5-yl)-2-hydroxydecanoamide (0.55 gm, 1.5mmol) was dissolved in 10 ml of methylene chloride, cooled to 0° C. andtreated with catalytic DMAP followed by TEA (0.25 ml, 1.8 mmol) and MsCl(0.14 ml, 1.8 mmol). The reaction was stirred for 2 hours and thenpoured into saturated NaHCO₃ (5 ml) and extracted with ethyl acetate (10ml). The organic layer was washed with brine, dried (MgSO₄) andconcentrated to a foam. The material was purified by silica gelchromatography using 80% ethyl acetate to hexane as the eluent.(2R)-N-(6-Methlythioquinolin-5-yl)-2-methanesulfonate decanoamide wasobtained (0.341 gm, 0.78 mmol, 52%).

¹ H NMR δ8.68 (d, 1H, J=2.8 Hz), 8.54 (s, 1H), 7.95 (d, 1H, J=8.4 Hz),7.21 (m, 1H), 5.11 (t, 1H, J=6.6 Hz), 3.05 (s, 3H), 2.33 (s, 3H),1.97-1.21 (m, 14H), 0.83 (t, 3H, J=6.63 Hz).

Hexanethiol (0.077' ml, 0.54 mmol) was dissolved in 2 ml of THF andtreated with KOtBu ((0.025 gm, 0.22 mmol) and the reaction stirred at rtfor 30 minutes. To the solution was added(2R)-N-(6-methlythioquinolin-5-yl)-2-methanesulfonatedecanoamide (0.08gm, 0.18 mmol) in 1 ml of THF and the reaction of THF and the reactionstirred at room temperature for 1 hour. The reaction was poured intosaturated NaHCO₃ (5 ml) and extracted with ethyl acetate (2×10 ml). Theorganic layer was washed with brine, dried (MgSO₄) and concentrated togive (2S-N-(6-methylthioquinolin-5-yl)-2-hexylthiodecanoamide as a whitesolid (0.68 gm, 0.147 mmol, 82%).

[α]_(D) =-17.74° (C=0.45, MeOH.

M.p. 86°-88° C.

EXAMPLE 268 (2S)-N-(6-Methylthioquinolin-5-yl)-2-phenylthiodecanoamide

Thiophenol (0.15 ml, 1.46 mmol) was dissolved in 5 ml of THF and cooledto 0° C. To this solution was added potassium t-butoxide (KOtBu) (0.084gm, 0.75 mmol) and the slurry was stirred for 30 minutes.(2R)-N-(6-Methylthioquinolin-5-yl)-2-methanesulfonatedecanoamide (0.218gm, 0.49 mmol) was dissolved in 2 ml of THF and added to the thiolsolution. The reaction was allowed to slowly warm to room temperatureand stirred for 2 hours. The reaction was poured into saturated NaHCO₃and extracted with ethyl acetate. The organic layer was washed withbrine, dried and concentrated to a crude oil. The oil was purified bysilica gel chromatography using 50% hexane/ethyl acetate as the eluentto yield (2S)-N-(6-methylthioquinolin-5-yl)-2-phenylthiodecanoamide as awhite solid (0.14 gm, 0.31 mmol, 63%).

M.p. 126°-128° C.

EXAMPLE 269 (2 S)-N-(6-Methylthioquinolin-5-yl)-2-Phenylthiodecanoamide

(2R)-N-(6-Methylthioquinol in-5-yl)-2-methanesulfonatedecanoamide (0.29gm, 0.66 mmol) and thiophenyl (0.13 ml, 1.26 mmol) were dissolved in 6ml of acetonitrile. To this solution was added tetramethyl quanidine(0.091 ml, 0.73 mmol) and the reaction stirred at room temperature for 2hours. The reaction was poured into NaHCO₃ (ml) and extracted with ethylacetate (2×10 ml). The organic layers were washed with brine, dried(MGSO₄) and concentrated to yield a crude solid that was crystallizedfrom 10 ml of acetonitrile to give(2S)-N-(6-methylthioquinolin-5-yl)-2-phenylthiodecanoamide as a whitesolid (0.168 gm, 0.37 mmol, 56%).

M.p. 128°-129° C. HRMS calc'd for C₂₆ H₃₂ ON₂ A₂, 452.1949. Found,452.1970.

We claim:
 1. A compound of the formula ##STR10## wherein R²¹ is (C₁ -C₃)alkyl and R²² is hydrogen or (C₁ -C₃)alkyl.
 2. A compound of formula ##STR11## wherein R²¹ is (C₁ -C₃)alkyl and R²² is hydrogen or (C₁ -C₃)alkyl, which contains a tracer amount of radiolabeling.
 3. The compound according to claim 2 wherein said radiolabel is selected from tritium and carbon-14.
 4. The compound according to claim 3 wherein said radiolabel is tritium.
 5. The compound according to claim 3 wherein said radiolabel is carbon-14. 